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Background and objectives: Correct identification of estrogen receptor (ER) status in breast cancer (BC) is crucial to optimize treatment; however, standard of care, involving biopsy and immunohistochemistry (IHC), and other diagnostic tools such as 2-deoxy-2-[18F]fluoro-D-glucose or 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), can yield inconclusive results. 16α-[18F]fluoro-17β-fluoroestradiol ([18F]FES) can be a powerful tool, providing high diagnostic accuracy of ER-positive disease. The aim of this study was to estimate the budget impact and cost-effectiveness of adding [18F]FES PET/CT to biopsy/IHC in the determination of ER-positive status in metastatic (mBC) and recurrent breast cancer (rBC) in the United States (US). Methods: An Excel-based decision tree, combined with a Markov model, was developed to estimate the economic consequences of adding [18F]FES PET/CT to biopsy/IHC for determining ER-positive status in mBC and rBC over 5 years. Scenario A, where the determination of ER-positive status is carried out solely through biopsy/IHC, was compared to scenario B, where [18F]FES PET/CT is used in addition to biopsy/IHC. Results: The proportion of true positive and true negative test results increased by 0.2 to 8.0 percent points in scenario B compared to scenario A, while re-biopsies were reduced by 94% to 100%. Scenario B resulted in cost savings up to 142 million dollars. Conclusions: Adding [18F]FES PET/CT to biopsy/IHC may increase the diagnostic accuracy of the ER status, especially when a tumor sample cannot be obtained, or the risk of a biopsy-related complication is high. Therefore, adding [18F]FES PET/CT to biopsy/IHC would have a positive impact on US clinical and economic outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Dysregulation of estrogen receptor alpha (ER) activity has been implicated in the development of resistance to current treatment strategies. The purpose of this study was to profile novel coregulatory proteins to identify potential therapeutic targets. We identified TRIM33 as a novel interactor and regulator of ER activity and protein stability. These results provide rationale for further investigation of the role of TRIM33 in cancers exhibiting increased ER protein levels. Estrogen receptor alpha (ER)-positive breast cancer is responsible for over 60% of breast cancer cases in the U.S. Among patients diagnosed with early-stage ER+ disease, 1/3 will experience recurrence despite treatment with adjuvant endocrine therapy. ER is a nuclear hormone receptor responsible for estrogen-driven tumor growth. ER transcriptional activity is modulated by interactions with coregulators. Dysregulation of the levels of these coregulators is involved in the development of endocrine resistance. To identify ER interactors that modulate transcriptional activity in breast cancer, we utilized biotin ligase proximity profiling of ER interactomes. Mass spectrometry analysis revealed tripartite motif containing 33 (TRIM33) as an estrogen-dependent interactor of ER. shRNA knockdown showed that TRIM33 promoted ER transcriptional activity and estrogen-induced cell growth. Despite its known role as an E3 ubiquitin ligase, TRIM33 increased the stability of endogenous ER in breast cancer cells. TRIM33 offers a novel target for inhibiting estrogen-induced cancer cell growth, particularly in cases of endocrine resistance driven by ER (ESR1) gene amplification or overexpression. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks specific targets such as estrogen, progesterone, and HER2 receptors. TNBC affects one in eight women in the United States, making up 15–20% of breast cancer cases. Patients with TNBC can develop resistance to chemotherapy over time, leading to treatment failure. Therefore, finding other options like natural products is necessary for treatment. The advantages of using natural products sourced from plants as anticancer agents are that they are less toxic, more affordable, and have fewer side effects. These products can modulate several cellular processes of the tumor microenvironment, such as proliferation, migration, angiogenesis, cell cycle arrest, and apoptosis. The phosphatidyl inositol 3-kinase (PI3K)-AKT signaling pathway is an important pathway that contributes to the survival and growth of the tumor microenvironment and is associated with these cellular processes. This current study examined the anticancer effects of fucoxanthin, a marine carotenoid isolated from brown seaweed, in the MDA-MB-231 and MDA-MB-468 TNBC cell lines. The methods used in this study include a cytotoxic assay, PI3K-AKT signaling pathway PCR arrays, and Wes analysis. Fucoxanthin (6.25 µM) + TNF-α (50 ng/mL) and TNF-α (50 ng/mL) showed no significant effect on cell viability compared to the control in both MDA-MB-231 and MDA-MB-468 cells after a 24 h treatment period. PI3K-AKT signaling pathway PCR array studies showed that in TNF-α-stimulated (50 ng/mL) MDA-MB-231 and MDA-MB-468 cells, fucoxanthin (6.25 µM) modulated the mRNA expression of 12 genes, including FOXO1, RASA1, HRAS, MAPK3, PDK2, IRS1, EIF4EBP1, EIF4B, PTK2, TIRAP, RHOA, and ELK1. Additionally, fucoxanthin significantly downregulated the protein expression of IRS1, EIF4B, and ELK1 in MDA-MB-231 cells, and no change in the protein expression of EIF4B and ELK1 was shown in MDA-MB-468 cells. Fucoxanthin upregulated the protein expression of RHOA in both cell lines. The modulation of the expression of genes and proteins of the PI3K-AKT signaling pathway may elucidate fucoxanthin's effects in cell cycle progression, apoptotic processes, migration, and proliferation, which shows that PI3K-AKT may be the possible molecular mechanism for fucoxanthin's effects. In conclusion, the results obtained in this study elucidate fucoxanthin's molecular mechanisms and indicate that fucoxanthin may be considered a promising candidate for breast cancer-targeted therapy. [ABSTRACT FROM AUTHOR]

Background HER2 immunohistochemistry (IHC) reproducibility is suboptimal for HER-low cases (IHC 1+ or 2+). Methods The Yale cohort included 214 stages I-II estrogen receptor positive breast cancers with IHC scores 0, 1+, and 2+ and routine Oncotype DX Recurrence Score (RS) results. The Exact Sciences (ES) cohort included 9 57 624 patients who had an Oncotype DX RS assay that assigns HER2-negative, equivocal, or positive status based on HER2 mRNA levels. Results HER2 mRNA levels varied across IHC categories but with increasing medians of 9.10 (n  = 89), 9.20 (n  = 71), and 9.45 (n  = 54) in IHC 0, 1+, and 2+, respectively. 22.4% of HER2-low (1+/2+) cancer had RS > 25. Over 98% of HER-low cancers were HER2-negative by Oncotype DX assignment. Conclusions Cancers with higher mRNA levels exist within IHC 0 and low categories, most of the HER2-low patients by IHC have low RS indicating no benefit from current adjuvant chemotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-equivocal cases represent around 15% of breast carcinomas, and 20–40% of them are HER2-amplified. The distinction between HER2-amplified and non-amplified cases is of great importance for patient management, and in this study, we investigated the performance of STRAT4 (a RT-qPCR platform) in the evaluation of HER2-equivocal cases. We compared this technique to the recommended methods (immunohistochemistry and in situ hybridization) for the evaluation of HER2-equivocal cases and non-equivocal HER2 cases. We found a 91.3% accuracy for the identification of HER2-positive tumors globally and 99.3% for that of non-equivocal HER2 cases, while the accuracy decreased to 80.7% for HER2-equivocal cases. Our results suggest that STRAT4 is not reliable for the evaluation of the HER2 amplification status in equivocal cases. Xpert Breast Cancer STRAT4 is a RT-qPCR platform that studies the mRNA expression of ESR1, PGR, MKI67 and ERBB2, providing a positive or negative result for each of these breast cancer biomarkers. Its concordance with immunohistochemistry (IHC) and in situ hybridization (ISH) has been previously demonstrated, but none of the previous works was focused on HER2-equivocal (2+) cases identified by IHC. Thus, we studied the concordance between IHC/ISH and STRAT4 results for 112 HER2 2+ IBC samples, using 148 HER2 0+, 1+ and 3+ (no-HER2 2+) samples for comparison. We found 91.3% accuracy for the determination of HER2 status globally, 99.3% for no-HER2 2+ samples and 80.7% for HER2 2+ samples. Regarding the other biomarkers, we obtained 96.4% accuracy for estrogen receptor, 84.1% for progesterone receptor and 58.2% for Ki67. Our results suggest that the use of ERBB2 mRNA for the evaluation of HER2 2+ cases is not a reliable reflex method to assess the ERBB2 amplification status. [ABSTRACT FROM AUTHOR]

Background Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diets with higher insulinemic potential increase the risk of invasive breast cancer. Objectives We aimed to prospectively evaluate the association between a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer. Methods We prospectively followed 76,686 women from the Nurses' Health Study (NHS; 1984–2016) and 93,287 women from the Nurses' Health Study II (NHSII; 1991–2017). Diet was assessed by food-frequency questionnaires every 4 y. The insulinemic potential of diet was evaluated using the previously established EDIH based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential of the diet. Covariates included reproductive, hormonal, and anthropometric factors (height and BMI at age 18 y); race; socioeconomic status; total alcohol intake; total caloric intake; and physical activity. Results During 4,216,106 person-years of follow-up, we documented 10,602 breast cancer cases (6689 NHS, 3913 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIH quintile (Q) were at higher breast cancer risk (HRQ5 vs. Q1 = 1.15; 95% CI: 1.07, 1.24; P -trend < 0.01). Although heterogeneity by estrogen receptor (ER) status was nonsignificant, the strongest association between EDIH and breast cancer was observed for ER-negative tumors (HRQ5 vs. Q1 = 1.21; 95% CI: 1.00, 1.46; P -trend = 0.02). Among tumor molecular subtypes, the strongest associations were observed for human epidermal growth factor receptor 2 (HER2)–enriched tumors (HRQ5 vs. Q1 = 1.62; 95% CI: 1.01, 2.61; P -trend = 0.02). Conclusions A dietary pattern contributing to hyperinsulinemia and insulin resistance was associated with greater breast cancer risk, especially ER-negative and HER2-enriched tumors. Our findings suggest that dietary modifications to reduce insulinemic potential may reduce the risk of breast cancer. [ABSTRACT FROM AUTHOR]

The article discusses a study published in "JAMA Network Open" which suggested that breast cancer risk assessment should start at an early age in non-Hispanic African American women to determine whether targeted screening should be recommended earlier in non-Hispanic African American women at high risk. Topics include comparison of the prognosis between young women and older women with breast cancer, increase in invasive breast cancer incidence, and limitations of the study.

The article discusses research on the link between exposure to residential ambient particle radioactivity (PR), a radiometric characteristic of airborne particulate matter, and breast cancer risk. The study measures the range of PR exposure among U.S. women diagnosed with breast cancer according to race, ethnicity and educational attainment. Hazard ratios and confidence intervals for the association of PR exposures with predictors of emissions were estimated per interquartiles and quintiles.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), organophosphate esters (OPEs), and polybrominated diphenyl ethers (PBDEs) are hormone-disrupting chemicals that migrate from building materials into air and dust. OBJECTIVES: We aimed to quantify the hormonal activities of 46 dust samples and identify chemicals driving the observed activities. METHODS: We evaluated associations between hormonal activities of extracted dust in five cell-based luciferase reporter assays and dust concentrations of 42 measured PFAS, OPEs, and PBDEs, transformed as either raw or potency-weighted concentrations based on Tox21 high-throughput screening data. RESULTS: All dust samples were hormonally active, showing antagonistic activity toward peroxisome proliferator-activated receptor (PPAR?2) (100%; 46 of 46 samples), thyroid hormone receptor (TRß) (89%; 41 samples), and androgen receptor (AR) (87%; 40 samples); agonist activity on estrogen receptor (ERa) (96%; 44 samples); and binding competition with thyroxine (T4) on serum transporter transthyretin (TTR) (98%; 45 samples). Effects were observed with as little as 4 µg of extracted dust. In regression models for each chemical class, interquartile range increases in potency-weighted or unknown-potency chemical concentrations were associated with higher hormonal activities of dust extracts (potency-weighted: ?PFAS–TRß, ? 28%, 푝 < 0.05; ?OPEs–TRß, ? 27%, 푝= 0.08; ?PBDEs–TRß, ? 20%, 푝< 0.05; ?PBDEs–ERa, ? 7.7%, 푝= 0.08; unknown-potency: ?OPEs–TTR, ? 34%, 푝< 0.05; ?OPEs–AR, ? 13%, 푝= 0.06), adjusted for chemicals with active, inactive, and unknown Tox21 designations. DISCUSSION: All indoor dust samples exhibited hormonal activities, which were associated with PFAS, PBDE, and OPE levels. Reporter gene cell-based assays are relatively inexpensive, health-relevant evaluations of toxic loads of chemical mixtures that building occupants are exposed to. [ABSTRACT FROM AUTHOR]

Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents. [ABSTRACT FROM AUTHOR]

Metals could act as endocrine disruptors that mimic the actions of hormones, such as estrogens, and contribute to the development and progression of breast cancer. In this study, we examined the association between ambient air emissions of several endocrine-disrupting metals and the incidence of female breast cancer in the United States by analyzing county-level data from national datasets. Linear regression analysis was conducted to evaluate the association in unadjusted and adjusted models. Of the metals analyzed, air emissions of arsenic, cadmium, lead, and mercury, but not chromium VI, were significantly associated with the incidence of all breast cancers, after adjusting for potential confounders. Emissions of arsenic, lead, and mercury were found to be significantly associated with the incidence of estrogen receptor (ER)-positive breast cancer. Among these metals, air emissions of lead showed the strongest association with breast cancer incidence with the β of 3756.66 (95% CI: 1660.29, 5853.03) for all breast cancers and 2433.85 (440.59, 4427.10) for ER-positive breast cancer. Our results demonstrate that exposure to endocrine-disrupting metals in ambient air may be associated with an increased incidence of breast cancer in the United States. Further studies are needed to explore these interactions and to elucidate mechanisms of action. [ABSTRACT FROM AUTHOR]

Almost two percent of individuals in the United States identify as gender non-conforming. In the female-to-male (FTM) transgender population, masculinizing hormone therapy with testosterone is commonly prescribed in gender transition. To date, the effects of exogenous androgens on breast tissue and its roles in altering breast cancer risk are poorly understood. This study examines the histopathologic findings in gender affirming mastectomy (GAM) in transgender FTM patients and the effects of exogenous androgens on estrogen receptors (ER) and androgen receptors (AR). A retrospective review of pathology specimens obtained between 2017 and 2020 was performed comparing androgen exposed breast tissue with breast tissue without androgen exposure. Breast specimens were obtained from patients who underwent FTM GAM with recorded exogenous androgen exposure. Control breast specimens were obtained from reduction mammoplasty (RM) procedures in cisgender women which were aged matched to the GAM cohort, as well as postmenopausal women with benign/prophylactic mastectomy procedures; all controls were without androgen exposure. The histopathologic findings were assessed. Immunohistochemistry for AR and ER was performed and the score interpreted by digital image analysis. Androgen-exposed breast tissue revealed dense fibrotic stroma, lobular atrophy, thickened lobular basement membranes, and gynecomastoid changes. Longer duration of androgen exposure resulted in a more pronounced effect. The incidence of atypia or cancer was lower in GAM than RM cohort. ER and AR expression was highest in transgender male breast tissue with intermediate duration of exogenous androgen exposure. Increased androgen exposure is associated with lobular atrophy and gynecomastoid changes in breast parenchyma. Overall, ER and AR are expressed strongly in lobular epithelium in patients with prolonged androgen exposure. Exogenous testosterone does not appear to increase risk for breast cancer. Additional studies are needed to investigate the mechanism responsible for these changes at a cellular level and its role in cancer development. • Exogenous androgen is associated with gynecomastoid changes in breast parenchyma. • Hormone receptors are expressed strongly with prolonged androgen exposure. • Exogenous androgen does not appear to increase risk for breast cancer in our cohort. • Standardized sampling protocol can decrease cost and burden on pathologists. [ABSTRACT FROM AUTHOR]

Abstract The widely used surfactant nonylphenol ethoxylate (NPEO) and its raw material 4-n-nonylphenol (4-n-NP), as well as its degradation products, are recognized as endocrine disrupting chemicals. The USA Environmental Protection Agency (EPA) released an assessment that looked for safe alternatives to NPEO. Vanillin ethoxylate (VAEO) is a novel substitute for NPEO and is quite similar to NPEO in structure; there is a risk that it has similar endocrine disrupting effects to NPEO. However, their effects on various nuclear hormone receptors have not been thoroughly examined. In this study, the effects of NPEO, VAEO, 4-n-NP and Vanillin on the estrogen receptor α (ERα), androgen receptor (AR), thyroid hormone receptor (TR), retinoic X receptor β (RXRβ) and estrogen-related receptor γ (ERRγ) were determined and compared using a battery of recombined yeast strains expressing β-galactosidase. The results showed that NPEO and 4-n-NP acted as significant antagonists of ER, AR, TR and ERRγ. In addition, 4-n-NP also had antagonistic activity toward RXRβ. Moreover, VAEO was shown to be a very weak antagonist of TR and ERRγ, and Vanillin had no interaction with any nuclear receptors. For the first time, it was found that NPEO had AR, TR and ERRγ antagonistic effects and that 4-n-NP was an antagonist of RXRβ. The in vitro data indicated that NPEO, 4-n-NP and VAEO have the potential to act as endocrine disruptors involving more than one nuclear hormone receptor, but VAEO has much lower endocrine disrupting potential than NPEO. Thus, it is critical to find safe substitutes for NPEO and a substitute of NPEO with structural analogues should be carried out with caution. Furthermore, to look for preferable alternatives for NPEO, more in vivo and in vitro studies of the alternatives concerning endocrine disruption are needed, especially in vitro studies need to involve various target points, not only focus on their effects on ER but also take other nuclear hormone receptor pathways into consideration. Highlights • For the first time, it was found that NPEO had AR, TR, and ERRγ antagonistic effects. • The novel alternative VAEO acted as a very weak antagonist of TR and ERRγ. • 4-n-NP acted as a significant antagonist of ER, AR, TR, RXRβ and ERRγ. • It was a novel finding that the antagonistic activity of 4-n-NP toward RXRβ. • More research would need to be done to find other safe substitutes for NPEO, due to VAEO against TR and ERRγ. [ABSTRACT FROM AUTHOR]

Background Many epidemiologic studies have analyzed the relations of individual foods and nutrients and breast cancer risk with inconsistent results. Few studies have examined recommendation-based dietary indices and breast cancer risk. Objective The aim of this study was to determine associations between recommendation-based dietary index scores and incident invasive breast cancer. Methods The Sister Study is a prospective cohort of 50,884 US women (baseline: 2003–2009) who had a sister with breast cancer but no prior breast cancer themselves. We created scores for the Dietary Approaches to Stop Hypertension (DASH) diet, Alternative Mediterranean Diet (AMED), and Alternative Healthy Eating Index–2010 (AHEI-2010) from dietary intakes estimated by a baseline-validated Block food-frequency questionnaire (FFQ). We used Cox regression to estimate multivariable-adjusted HRs and 95% CIs for total invasive breast cancer risk and by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status. Results We documented 1,700 invasive breast cancer cases through 2015 (mean follow-up, 7.6 y). Individuals in the highest quartile of DASH scores had a lower risk of invasive breast cancer compared with those in the lowest quartile (HR: 0.78; 95% CI: 0.67, 0.90; P -trend = 0.001), with stronger associations for ER– (HR: 0.61; 95% CI: 0.40, 0.94; P -trend = 0.006) as well as ER–/PR– and ER–/PR–/HER2– subtypes. AHEI-2010 (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.78, 1.03; P -trend = 0.15) and AMED (HR for highest compared with lowest quartile: 0.90; 95% CI: 0.77, 1.06; P -trend = 0.07) were weakly and nonsignificantly associated with breast cancer risk, but after excluding alcohol, AHEI-2010 was inversely associated with risk of ER–/PR– (HR: 0.64; 95% CI: 0.42, 0.98; P -trend = 0.04) and ER–/PR–/HER2– subtypes. We did not observe any significant interactions by menopausal status or other participant characteristics. Conclusions DASH scores were inversely associated with breast cancer risk; DASH and AHEI-2010 scores excluding alcohol were particularly inversely associated with risk of ER–/PR– and ER–/PR–/HER2– breast cancers. This trial was registered at clinicaltrials.gov as NCT00047970. [ABSTRACT FROM AUTHOR]

Background: Although people living with HIV or AIDS (PLWHA) are at higher risk for many cancers, breast, prostate, and colorectal cancer rates are lower in this patient population. Because these tumors are often screen-detected, these inverse associations could be driven by HIV-related differences in utilization of cancer screening.Methods: We ascertained incident breast, prostate, and colorectal cancer in PLWHA using data from the HIV/AIDS Cancer Match Study (1996-2012). Comparisons with general population cancer rates were made using standardized incidence ratios (SIRs), overall and stratified by tumor stage/size, breast cancer estrogen receptor status, and colorectal site. We also examined the potential effect of study design and unmeasured confounding on inverse standardized incidence ratios.Results: Compared with the general population, PLWHA had lower rates of invasive breast (SIR = 0.63, 95% confidence interval [CI] = 0.58 to 0.68), prostate (SIR = 0.48, 95% CI = 0.46 to 0.51), proximal colon (SIR = 0.67, 95% CI = 0.59 to 0.75), distal colon (SIR = 0.51, 95% CI = 0.43 to 0.59), and rectal cancers (SIR = 0.69, 95% CI = 0.61 to 0.77). Reduced risk persisted across tumor stage/size for prostate and colorectal cancers. Although distant-stage breast cancer rates were not reduced (SIR = 0.94, 95% CI = 0.73 to 1.20), HIV-infected women had lower rates of large (>5 cm) breast tumors (SIR = 0.65, 95% CI = 0.50 to 0.83). The magnitude of these inverse standardized incidence ratios could not plausibly be attributed to case underascertainment, out-migration, or unmeasured confounding.Conclusions: Breast, prostate, and colorectal cancer rates are markedly lower among PLWHA, including rates of distant-stage/large tumors that are not generally screen-detected. This set of inverse HIV-cancer associations is therefore unlikely to be due primarily to differential screening and may instead represent biological relationships requiring future investigation. [ABSTRACT FROM AUTHOR]

Evidence suggests that contemporary population distributions of estrogen-receptor (ER) status among breast cancer patients may be shaped by earlier major societal events, such as the 1965 abolition of legal racial discrimination in the United States (state and local "Jim Crow" laws) and the Great Famine in China (1959-1961). We analyzed changes in ER status in relation to Jim Crow birthplace among the 46,417 black and 339,830 white US-born, non-Hispanic women in the Surveillance, Epidemiology, and End Results (SEER) 13 Registry Group who were born between 1915 and 1979 and diagnosed (ages 25-84 years, inclusive) during 1992-2012. We grouped the cases according to birth cohort and quantified the rate of change using the haldane (which scales change in relation to biological generation). The percentage of ER-positive cases rose according to birth cohort (1915-1919 to 1975-1979) only among women diagnosed before age 55. Changes according to biological generation were greater among black women than among white women, and among black women, they were greatest among those born in Jim Crow (versus non-Jim Crow) states, with this group being the only group to exhibit high haldane values (>10.31, indicating high rate of change). Our study's analytical approach and findings underscore the need to consider history and societal context when analyzing ER status among breast cancer patients and racial/ethnic inequities in its distribution. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the impact of race and socioeconomic status on breast tumor clinicopathological features and survival outcomes. This study used breast cancer data from the Washington D.C. Cancer Registry (2000-2010). Logistic regression and survival analysis assessed the association between race, socioeconomic (SES) variables, clinicopathological variables, recurrence-free survival and overall survival. African American (AA) breast cancer patients had an increased risk for stage III, ER-, and PR- breast cancer compared with White and Hispanic breast cancer patients. Additionally, D.C. geographical areas of lower socioeconomic status had higher incidences of stage III and stage IV breast cancer. A nested analysis demonstrated that AAs with higher median incomes compared with AAs with lower incomes revealed no differences for clinicopathological variables, nor were differences found between overall and recurrence-free survival. This study suggests that the biology of breast cancer in AAs could be driving breast cancer disparities. [ABSTRACT FROM AUTHOR]

[Display omitted] • Bottled water (BW) consumption increasing, with public-supply drinking water concerns. • Directly comparable, broad contaminant-mixture exposure assessments lacking for BW. • 465 organics/53 inorganics/14 microbial indicators/1 bioactivity assessed in 30 BW. • 48 inorganics/45 organics were detected, and benchmark screening levels were exceeded. • Contaminant mixtures of potential human-health concern also common in BW. Bottled water (BW) consumption in the United States and globally has increased amidst heightened concern about environmental contaminant exposures and health risks in drinking water supplies, despite a paucity of directly comparable, environmentally-relevant contaminant exposure data for BW. This study provides insight into exposures and cumulative risks to human health from inorganic/organic/microbial contaminants in BW. BW from 30 total domestic US (23) and imported (7) sources, including purified tapwater (7) and spring water (23), were analyzed for 3 field parameters, 53 inorganics, 465 organics, 14 microbial metrics, and in vitro estrogen receptor (ER) bioactivity. Health-benchmark-weighted cumulative hazard indices and ratios of organic-contaminant in vitro exposure-activity cutoffs were assessed for detected regulated and unregulated inorganic and organic contaminants. 48 inorganics and 45 organics were detected in sampled BW. No enforceable chemical quality standards were exceeded, but several inorganic and organic contaminants with maximum contaminant level goal(s) (MCLG) of zero (no known safe level of exposure to vulnerable sub-populations) were detected. Among these, arsenic, lead, and uranium were detected in 67 %, 17 %, and 57 % of BW, respectively, almost exclusively in spring-sourced samples not treated by advanced filtration. Organic MCLG exceedances included frequent detections of disinfection byproducts (DBP) in tapwater-sourced BW and sporadic detections of DBP and volatile organic chemicals in BW sourced from tapwater and springs. Precautionary health-based screening levels were exceeded frequently and attributed primarily to DBP in tapwater-sourced BW and co-occurring inorganic and organic contaminants in spring-sourced BW. The results indicate that simultaneous exposures to multiple drinking-water contaminants of potential human-health concern are common in BW. Improved understandings of human exposures based on more environmentally realistic and directly comparable point-of-use exposure characterizations, like this BW study, are essential to public health because drinking water is a biological necessity and, consequently, a high-vulnerability vector for human contaminant exposures. [ABSTRACT FROM AUTHOR]

Background: The Cancer and Leukemia Group B (CALGB) 9343 trial demonstrated that adjuvant radiation therapy (RT) can be omitted in women aged 70 years or older, with small, estrogen receptor (ER)+ breast cancer. We postulated that RT usage after CALGB's publication should have decreased over time.Study Design: We evaluated a cohort of 205,860 women aged 70 years or older, with stage I, ER+/progesterone receptor (PR)+ breast cancer with lumpectomy, diagnosed between 1998 and 2012, in the National Cancer Data Base. Clinicopathologic and sociodemographic variables were compared between pre-CALGB and post-CALGB publication (circa 2004). Univariate and multivariate analysis were used.Results: Radiation therapy usage decreased by only 2.95% after CALGB publication (68.71% vs 65.76%; p < 0.0001). Almost one-third of women with short life expectancy (≥85 years) received RT in the post-CALGB group. Significant predictors (p < 0.01) of lowest RT use include advanced age, increased great circle distance, academic research program, East South Central region, rural population < 2,500 not adjacent to a metropolitan area, low income level, high comorbidity index, small tumor, well-differentiated histology, residual tumor, and lack of receipt of anti-hormonal therapy.Conclusions: The CALGB trial had a minimal impact on the rate of adjuvant RT use among elderly women with small, hormone positive breast cancers. Significant variation in RT usage exists across sociodemographic strata. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of death in the United States. Despite its slow development and the capacity for early diagnosis, current preventive approaches are not sufficient. However, a role for estrogen has been demonstrated in multiple epidemiologic studies, which may benefit CRC prevention. A large body of evidence from preclinical studies indicates that expression of the estrogen receptor beta (ERβ/ESR2) demonstrates an inverse relationship with the presence of colorectal polyps and stage of tumors, and can mediate a protective response. Natural compounds, including phytoestrogens, or synthetic ERβ selective agonists, can activate or upregulate ERβ in the colon and promote apoptosis in preclinical models and in clinical experience. Importantly, this activity has been associated with a reduction in polyp formation and, in rodent models of CRC, has been shown to lower incidence of colon adenocarcinoma. Collectively, these findings indicate that targeted activation of ERβ may represent a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this condition. In this review, we discuss the potential of new chemopreventive or dietary approaches based on estrogen signaling. [ABSTRACT FROM AUTHOR]

The article discusses various preventive measures for colorectal adenomas (CRC) which is the fourth most common type of cancer in the U.S. Topics include hormone replacement therapy (HRT) which has a protective function in preventing CRC, role of oestrogen receptors in colon carcinogenesis, and the function of lignans in colorectal carcinogenesis.

Breast cancer is the second leading cause of death among women in the United States. Estrogens have been implicated as major risk factors in the development of breast neoplasms. Recent epidemiologic studies have suggested a protective role of phytoestrogens in prevention of breast and other cancers. Resveratrol, a naturally occurring phytoestrogen found notably in red grapes, berries and peanuts, has been shown to possess potent anti-cancer properties. However, the poor efficacy of resveratrol has prevented its use in a clinical setting. In order to improve the efficacy of resveratrol, we have synthesized a small combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the growth of breast cancer cell lines. We have recently shown that one of the synthesized analogs, 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD), has better anti-cancer properties than resveratrol. The objective of this study was to investigate the differential regulation of estrogen receptors (ERs) α and β as a potential mechanism of inhibition of breast cancer by HPIMBD. Estrogen receptors α and β have been shown to have opposing roles in cellular proliferation. Estrogen receptor α mediates the proliferative responses of estrogens while ERβ plays an anti-proliferative and pro-apoptotic role. We demonstrate that HPIMBD significantly induces the expression of ERβ and inhibits the expression of ERα. HPIMBD also inhibits the protein expression levels of oncogene c-Myc and cell cycle protein cyclin D1, genes downstream to ERα and important regulators of cell cycle, and cellular proliferation. HPIMBD significantly induces protein expression levels of tumor suppressors p53 and p21 in MCF-7 cells. Additionally, HPIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this novel compound. Molecular docking studies confirm higher affinity for binding of HPIMBD in the ERβ cavity. Thus, HPIMBD, a novel azaresveratrol analog may inhibit the proliferation of breast cancer cells by differentially modulating the expressions of ERs α and β. [ABSTRACT FROM AUTHOR]

Due to the high incidence of breast cancer in the United States, optimal strategies for its prevention are imperative. This entails identification of women who are at an increased risk for breast cancer and an integrative approach that includes effective screening methods as well as nutritional, pharmacologic, and surgical management. Several breast cancer risk-assessment tools, such as the Gail and Claus models, can help clinicians determine the quantitative risk of breast cancer. The role of selective estrogen receptor modulators, such as tamoxifen and raloxifene, for the prevention of breast cancer has been well established. Several other agents, such as aromatase inhibitors, are currently being investigated. The potential adverse effects of these chemopreventive agents, which include an impact on the quality of life, must be discussed with the patient before deciding on this approach. Additionally, breast cancer risk factors have been identified over the years; some of them are modifiable, but others are not. Although there is no conclusive evidence to suggest the protective role of specific dietary components, alcohol consumption and obesity are associated with an increased breast cancer risk; thus lifestyle changes can lead to a lower risk of developing breast cancer. Surgical approaches, including bilateral risk-reduction mastectomy and salpingo-oophorectomy, are usually limited to women with a hereditary predisposition to development of breast cancer. The objective of this review is to summarize the various approaches directed at reducing the incidence of breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer remains the most common cancer diagnosed in women in the United States and is second only to lung cancer as a cause of cancer mortality. Breast cancer has become the prototypical solid tumor where targets have been identified within the tumor allowing for a personalized approach of systemic therapy. [ABSTRACT FROM AUTHOR]

AbstractTraumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17β-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously 1 hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5 mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER. [ABSTRACT FROM AUTHOR]

Abstract: Although breast cancer incidence in the US is highest for women of European ancestry (EA), women of African ancestry (AA) have higher incidence of cancer diagnosed before age 40 and tumors with more aggressive features (high grade and negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2)), which precludes targeted therapies and leads to poorer outcomes. It is unclear what underlies these disparities. It has been hypothesized that dark skin with high melanin content is the ancestral skin color of origin, with adaptation to northern environs resulting in lighter skin. Although intense sunlight in sub-Saharan Africa may compensate for low sun absorption through skin, an urban or western lifestyle may result in less synthesis of vitamin D with higher skin pigmentation. Laboratory and preclinical data indicate that vitamin D is involved in preventing breast carcinogenesis and progression. Vitamin D receptor (VDR) knock-out mice are more likely to develop tumors that are ER-negative, and we have shown that serum levels of 25OHD are lowest among EA women with triple-negative tumors (negative for ER, PR and HER2); and among non-cancer patients, vitamin D levels are lower in AAs than in EAs. Thus, it is plausible to hypothesize that low vitamin D levels could be associated with the higher prevalence of more aggressive tumors among AA women. In this paper, we review the current literature on vitamin D and aggressive breast cancer subtypes, discuss vitamin D in AA women from a perspective of evolution and adaption, and examine the potential role of vitamin D in cancer racial disparities. We present our recently published data showing two single nucleotide polymorphisms in vitamin D catabolic enzyme CYP24A1 associated with higher risk of estrogen ER-negative risk in AA than in EA women. The relationship of vitamin D with breast cancer risk may be subtype-specific, with emerging evidence of stronger effects of vitamin D for more aggressive breast cancer, particularly in women of African ancestry. [Copyright &y& Elsevier]

The article presents a population-based study which investigates the hormone receptor (HR) and HER2 expression among Kurdish women and Arabic women, and compares it with the U.S. Surveillance Epidemiology and End Result (SEER) data. The study reveals that low age standardized and age specific breast cancer incidence rates were found in Kurdish women compared to the U.S. It also shows that the majority of breast cancer was ER+/HER2-.

Background The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)–positive cancers. Time trends provide important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data. Methods We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program during 1980–2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age–period–cohort models. Results The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007–2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007–2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009–2016. Conclusion Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level. [ABSTRACT FROM PUBLISHER]

Abstract: Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC. [Copyright &y& Elsevier]

Abstract: Toxic effects evidenced in the environment are most often caused by mixtures of known and unknown pollutants. One of the key challenges in environmental chemistry and ecotoxicology is to characterize and identify those toxicants in relation with the effect. However, many of the current bottlenecks in the assessment of organic contaminants in our environment are related to the difficulty of evaluating various chemical classes and biological effects within complex mixtures and more precisely to link both approaches. To tackle these analytical challenges, the bioanalytical concept has emerged during the last decade. In this article, we describe through some outstanding examples the current limitations in the chemical-driven approach such as problems encountered for a correct evaluation of water quality when the continuous introduction of new chemicals has to be taken into account in monitoring for correct evaluation of this quality and could led to tremendous analytical costs or some of the integrated bioanalytical approaches as promising powerful tools to improve environmental risk assessment by taking into account the link presence/effect. [Copyright &y& Elsevier]

Nicotine addiction produces diverse physiological effects common to both men and women because of activation of the nicotinic acetylcholine receptors. In addition to these effects, nicotine reduces circulating estrogen (the female sex hormone) levels and leads to early onset of menopause in women. Nicotine's effect on estrogen metabolism has potential far-reaching consequences because endogenous circulating estrogen helps prevent cerebrovascular diseases in premenopausal women. In this article, the author presents a survey of literature showing that nicotine addiction causes unique deleterious effects in women's brains by inhibiting estrogen signaling, which makes the brain more susceptible to ischemic brain damage. [ABSTRACT FROM AUTHOR]

Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ERα and ERβ. Though the receptors have similar ligand binding and DNA binding domains, ERα and ERβ have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and nongenomic ER activity through direct interactions with ERs, indirectly through transcription factors such as the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism. Many EDCs act through multiple mechanisms as exemplified by chemicals that bind both AhR and ER, such as 3-methylcholanthrene. Other EDCs that target ER signaling include phytoestrogens, bisphenolics, and organochlorine pesticides, and many alter normal ER signaling through multiple mechanisms. EDCs can also display tissue-selective ER agonist and antagonist activities similar to selective estrogen receptor modulators (SERMs) designed for pharmaceutical use. Thus, biological effects of EDCs need to be carefully interpreted because EDCs can act through complex tissue-selective modulation of ERs and other signaling pathways in vivo. Current requirements by the U.S. Environmental Protection Agency require some in vitroand cell-based assays to identify EDCs that target ER signaling through direct and metabolic mechanisms. Additional assays may be useful screens for identifying EDCs that act through alternative mechanisms prior to further in vivostudy. [ABSTRACT FROM AUTHOR]

In the U.S., cancer is a disease of aging. The average 65-year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. However, older breast cancer patients can present with wide variations in health status, and treatment in older patients should therefore include a careful evaluation of comorbidities, physical function, polypharmacy, and other issues that could potentially impact a patient's ability to undergo chemotherapy without excessive risk. Evaluation tools are under development, including potential molecular markers, to identify which older patients are the best candidates for chemotherapy, as well as those more susceptible to actually developing cancer. Standard chemotherapy regimens are just as effective in older patients as they are in the younger population, and can substantially prolong life expectancy when used in the right patients. This article discusses breast cancer in seniors, including the epidemiology of breast cancer in these patients, the potential impact of comorbidities, and effective adjuvant therapy in selected older patients. [ABSTRACT FROM AUTHOR]

Reproductive abnormalities in alligators exposed to contaminants in Lake Apopka, Florida, USA represent a clear example of endocrine disruption in wildlife. Several of these contaminants that are not able to bind to mammalian estrogen receptors (such as atrazine and cyanazine) have previously been reported to bind to the alligator estrogen receptor from oviductal tissue. Binding of known Lake Apopka contaminants to full length estrogen receptors alpha from human (hERα) and alligator (aERα) was assessed in a side-by-side comparison within the same assay system. Baculovirus-expressed recombinant hERα and aERα were used in a competitive binding assay. Atrazine and cyanazine were not able to bind to either receptor. p,p′-Dicofol was able to bind to aERα with a concentration inhibiting 50% of binding (IC50) of 4 µM, while only partially displacing 17β-estradiol (E2) from hERα and yielding a projected IC50 of 45 µM. Chemicals that only partially displaced E2 from either receptor, including some dichlorodiphenyltrichloroethane (DDT) metabolites and trans-nonachlor, appeared to have higher affinity for aERα than hERα. p,p′-Dicofol-mediated transcriptional activation through aERα and hERα was assessed to further explore the preferential binding of p,p′-dicofol to aERα over hERα. p,p′-Dicofol was able to stimulate transcriptional activation in a similar manner with both receptors. However, the in vitro results obtained with p,p′-dicofol were not reflected in an in vivo mammalian model, where Kelthane™ (mixed o,p′- and p,p′-dicofol isomers) did not elicit estrogenic effects. In conclusion, although there was no evidence of exclusively species-specific estrogen receptor binders, some xenoestrogens, especially p,p′-dicofol, had a higher affinity for aERα than for hERα. Environ. Toxicol. Chem. 2010;29:2064–2071. © 2010 SETAC [ABSTRACT FROM AUTHOR]

In the United States, breast cancer is among the most frequently diagnosed cancers in women. Breast cancer is classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including the expression of hormone receptors (estrogen receptor and/or progesterone receptor) and/or HER2. Primary breast cancer treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine therapy, and/or targeted therapy. Endocrine therapy has been shown to be effective in hormone receptor-positive breast cancers and is a common choice for adjuvant therapy. However, due to the aggressive nature of triple-negative breast cancer, targeted therapy is becoming a noteworthy area of research in the search for non-endocrine-targets in breast cancer. In addition to HER2-targeted therapy, other emerging therapies include immunotherapy and targeted therapy against critical checkpoints and/or pathways in cell growth. This review summarizes novel targeted breast cancer treatments and explores the possible implications of combination therapy. [ABSTRACT FROM AUTHOR]

The third-generation aromatase inhibitors (AIs), anastrozole, exemestane, and letrozole are potential agents for preventing estrogen receptor (ER)-positive breast cancer (BC) in high-risk postmenopausal women. No AI has yet been fully evaluated for prevention. Each AI is incorporated into the design of a phase 3 randomized BC prevention trial based on hypothesis-generating contralateral breast cancer (CLBC) data from a corresponding adjuvant trial. Arimidex, tamoxifen alone or in combination (ATAC) pitted anastrozole against tamoxifen for 5 years as “initial adjuvant” therapy, showing at 33.3 months fewer CLBCs with anastrozole versus tamoxifen (odds ratio [OR] 0.42 overall; OR 0.29 ER-positive BCs), offering the hypothesis on which IBIS-II (International Breast Cancer Intervention Study) is based. “High-risk” IBIS-II compares anastrozole to placebo for the primary prevention of BC in 6000 postmenopausal women. IES (Intergroup Exemestane Study) compared exemestane to tamoxifen following 2–3 years of adjuvant tamoxifen in 4742 postmenopausal women with ER-positive BCs. The benefit from “switching” to exemestane in reducing CLBCs (HR 0.44 at 30.6 months) underlies MAP.3 (Mammary Prevention 3), which compares exemestane to placebo for primary BC risk reduction in 4560 postmenopausal women. MA.17 showed reduced CLBC incidence (HR 0.57) at 2.4 years in postmenopausal women with receptor-positive tumors receiving “extended adjuvant” letrozole compared to placebo following 5 years of tamoxifen. The Study of Letrozole and Raloxifene (STELLAR), using as the control raloxifene, the new U.S. standard drug for BC prevention, would complete the trio of AI prevention trials, but STELLAR is currently on hold. [ABSTRACT FROM AUTHOR]

Background: Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. Methodology/Principal Findings: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. Conclusions/Significance: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation. [ABSTRACT FROM AUTHOR]

The article discusses the role of endocrine disruptors in causing medical problems. Endocrine disruptors are industrial pollutants that mimic body hormones and disrupt the endocrine systems that are important in sexual development. Despite increasing concern over experimental research showing endocrine disruption in animals and epidemiological studies suggesting the negative effects of endocrine disruptors on human reproduction, the U.S. government failed to regulate these chemicals. Debates in the 1930s and 1940s over the regulation of diethylstilbestrol (DES) are discussed. DES are the first synthetic estrogen and the first chemical known to act as endocrine disruptor.

BACKGROUND: The deleterious impact of uranium on human health has been linked to its radioactive and heavy metal-chemical properties. Decades of research has defined the causal relationship between uranium mining/milling and onset of kidney and respiratory diseases 25 years later. OBJECTIVE: We investigated the hypothesis that uranium, similar to other heavy metals such as cadmium, acts like estrogen. METHODS: In several experiments, we exposed intact, ovariectomized, or pregnant mice to depleted uranium in drinking water [ranging from 0.5 μg/L (0.001 μM) to 28 mg/L (120 μM). RESULTS: Mice that drank uranium-containing water exhibited estrogenic responses including selective reduction of primary follicles, increased uterine weight, greater uterine luminal epithelial cell height, accelerated vaginal opening, and persistent presence of cornified vaginal cells. Coincident treatment with the antiestrogen ICI 182,780 blocked these responses to uranium or the synthetic estrogen diethylstilbestrol. In addition, mouse dams that drank uranium-containing water delivered grossly normal pups, but they had significantly fewer primordial follicles than pups whose dams drank control tap water. CONCLUSIONS: Because of the decades of uranium mining/milling in the Colorado plateau in the Four Corners region of the American Southwest, the uranium concentration and the route of exposure used in these studies are environmentally relevant. Our data support the conclusion that uranium is an endocrine-disrupting chemical and populations exposed to environmental uranium should be followed for increased risk of fertility problems and reproductive cancers. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown tamoxifen to be effective only in women with estrogen receptor (ER)-positive tumors, in a previous model, trends in the utilization of adjuvant therapy were modeled only as a function of age and stage of the disease and not ER status. In this paper, we integrate this previous estimate on the use of adjuvant systemic therapy for breast cancer in the United States with information on ER status from the Patterns of Care (POC) data to estimate the dissemination of adjuvant therapy for women with different ER-status tumors. We also summarize efficacy of adjuvant systemic therapy reported in the over- views of early breast cancer clinical trials. These two inputs, dissemination and efficacy, are key pieces for models that investigate the effect of breast cancer adjuvant therapy on the decline of U.S. breast cancer mortality. Methods: The adjustments to the previous models are calculated using the POC data on 7116 women with breast cancer diagnosed from 1987 to 1991 and in 1995 who were randomly selected from the Surveillance, and Epidemiology, and End Results (SEER) program registries. The POC data provide more accurate information on treatment and clinical variables (e. g., ER status) than the SEER data because medical records are reabstracted and further verified with treating physicians. Results: Use of multiagent chemotherapy is higher for younger women, (<50 years) and for women whose tumors were shown to be ER negative or borderline. The use of tamoxifen is higher among older women and women with ER-positive tumors. After 1980 the combined use of multiagent chemotherapy and tamoxifen for women diagnosed with breast cancer at ages 69 or younger increased more for women whose tumors were ER status positive or unknown than ER status negative. Older women (>69 years) seem to receive almost exclusively tamoxifen irrespective of ER status, except for a small percentage of those with more advanced stages (II- and II+/IIIA) who also receive multiagent chemotherapy. Discussion: The estimated dissemination trends by ER status, based on modeling the POC data, reveal that treatment strategies with demonstrated efficacy in clinical trials have been adopted into practice. The dissemination and efficacy are the two factors necessary to input into models to determine the population impact of these therapies on U.S. breast cancer mortality. The largest decline in mortality would be expected for younger women (<60 years) with ER-positive tumors or whose tumors are of unknown status because of the largest efficacy and dissemination of adjuvant therapy in this group. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated potential associations between single nucleotide polymorphism (SNP) variants of the estrogen receptor genes ESR1 and ESR2 and circulating estradiol (E2) concentrations in women of 4 races/ethnicities. The study population was drawn from participants in the Study of Women’s Health Across the Nation (SWAN). A total of 1,538 African American, Caucasian, Chinese, and Japanese women from SWAN participated in the Sex Steroid Hormone Genetics Protocol by providing blood for sex steroid hormone analyses and consenting to lymphocyte transformation from which DNA was extracted and genotyped. We evaluated 4 ESR1 SNPs (ESR1 rs9340799, ESR1 rs2234693, ESR1 rs728524, and ESR1 rs3798577), and 3 ESR2 SNPs (ESR2 rs1255998, ESR2 rs1256030, and ESR2 rs1256065). Mean E2 level was 196.0 ± 4.0 pmol/L in women who were premenopausal and perimenopausal (with blood drawn on days 2 through 5 of the menstrual cycle follicular phase); however, mean E2 levels in Chinese and Japanese women were lower (155.7 ± 10.6 pmol/L and 170.0 ± 10.3 pmol/L, respectively) than in African American (196.4 ± 8.1 pmol/L, P <0.05) or Caucasian women (210.7 ± 5.9 pmol/L, P <0.002). The ESR1 rs3798577 CC genotype was associated with lower circulating E2 concentrations in African American women (P <0.07) and explained about 1% of the variation in circulating E2 concentrations. In Japanese women, the GC genotype of ESR2 rs1255998 was associated with significantly lower circulating E2 concentrations that explained about 4% of the variation. Circulating E2 concentrations were not strongly or consistently associated with selected polymorphisms for the estrogen receptor genes. The 2 strongest associations explained <4% of the total variation in the circulating E2 concentrations. [Copyright &y& Elsevier]

Context: Breast augmentation is not associated with an increased risk of breast cancer; however, implants may interfere with the detection of breast cancer thereby delaying cancer diagnosis in women with augmentation. Objective: To determine whether mammography accuracy and tumor characteristics are different for women with and without augmentation. Design, Setting, and Participants: A prospective cohort of 137 women with augmentation and 685 women without augmentation diagnosed with breast cancer between January 1, 1995, and October 15, 2002, matched (1:5) by age, race/ethnicity, previous mammography screening, and mammography registry, and 10 533 women with augmentation and 974 915 women without augmentation and without breast cancer among 7 mammography registries in Denver, Colo; Lebanon, NH; Albuquerque, NM; Chapel Hill, NC; San Francisco, Calif; Seattle, Wash; and Burlington, Vt. Main Outcome Measures: Comparison between women with and without augmentation of mammography performance measures and cancer characteristics, including invasive carcinoma or ductal carcinoma in situ, tumor stage, nodal status, size, grade, and estrogen-receptor status. Results: Among asymptomatic women, the sensitivity of screening mammography based on the final assessment was lower in women with breast augmentation vs women without (45.0% [95% confidence interval {CI}, 29.3%-61.5%] vs 66.8% [95% CI, 60.4%-72.8%]; P = .008), and specificity was slightly higher in women with augmentation (97.7% [95% CI, 97.4%-98.0%] vs 96.7% [95% CI, 96.6%-96.7%]; P<.001). Among symptomatic women, both sensitivity and specificity were lower for women with augmentation compared with women without but these differences were not significant. Tumors were of similar stage, size, estrogen-receptor status, and nodal status but tended to be lower grade (P = .052) for women with breast augmentation vs without. Conclusions: Breast augmentation decreases the sensitivity of screening mammography among asymptomatic women but does not increase the false-positive rate. Despite the lower accuracy of mammography in women with augmentation, the prognostic characteristics of tumors are not influenced by augmentation. [ABSTRACT FROM AUTHOR]

The advantages that regular consumption of a diet containing soy may have on human health have been enshrined in a major health claim that has been approved by the Food and Drug Administration in the USA, regarding potential protection from heart disease by soy. This could have a major influence on the dietary consumption patterns of soy for consumers and lead to the development of soy enriched foods to enable consumers to achieve the benefits thought to be associated with increased soy consumption in a Western diet. If an increase in soy consumption is beneficial to particular disease conditions, there is always the possibility that there will be effects other than those that are desirable. For soy-containing foods there has been concern that the phytoestrogen content of soy, which is composed of several isoflavones, could be a separate health issue, due to the oestrogen-like activity of isoflavones. To address this, a method has been developed to estimate, relative to 17-β oestradiol, the activity of the common isoflavones present in soy phytoestrogens, based on their binding to and transcriptional activation of the major oestrogen receptor sub-types alpha and beta. Using this approach, the additional oestrogen-like activity that would be expected from inclusion of soy supplemented foodstuffs in a Western diet, can be determined for different sub-populations, who may have different susceptibilities to the potential for the unwanted biological effects occurring with consumption of soy enriched foods. Because of the theoretical nature of this model, and the controversy over the nature of whether some of the oestrogen-like effects of phytoestrogens are adverse, the biological effects of soy isoflavones and their potential for adverse effects in man, is also reviewed. The question that is critical to the long term safe use of foods enriched in soy is, which observed biological effects in animal studies are likely to also occur in man and whether these would have an adverse effect on human health. [Copyright &y& Elsevier]

Objective. Estrogen receptor 1 (ESR1) plays an important role in various estrogen-related diseases, the incidences of which are significantly lower in the Japanese population than in Western populations. We hypothesize that polymorphisms in exon 1 of the ESR1 gene are associated with a lower incidence of estrogen-related diseases in the Japanese population. Methods. The genetic distributions of six different ESR1 gene polymorphisms were investigated among 200 Japanese, 200 Americans and 112 Germans using a novel sequence-specific polymerase chain reaction (SSP) technique and direct DNA sequencing. Results. The frequencies of variant genotypes on codons 10 and 87 located on exon 1 were significantly lower in the Japanese population than other populations. The polymorphism on codon 87 was not detected in the Japanese population, although other populations showed the homozygous and heterozygous variant genotype on this codon. Other loci, intron 1, and codons 243 and 594 were not different among these populations. Conclusions. This is the first report to demonstrate the polymorphisms at codons 10 and 87 of ESR1 are significantly low for the Japanese population. Thus, inherited alterations in ESR1 polymorphisms may be associated with changes of estrogen effects and, thereby, may possibly explain inter-population differences in incidences of estrogen-mediated diseases. [ABSTRACT FROM AUTHOR]

Explores medical treatment options available for menopausal women in the United States. Hormone replacement therapy; Selective estrogen-receptor modulators; Nonhormonal management of menopausal symptoms; Botanical alternatives for menopausal symptoms.

The National Institute of Environmental Health Sciences (NIEHS) and the U.S. Environmental Protection Agency (U.S. EPA) recently cosponsored the Endocrine Disruptors Low-Dose Peer Review. The purpose of this meeting was to examine data supporting the presence or absence of low-dose effects of endocrine disruptors in specific studies and then to evaluate the likelihood and significance of these and/or other potential low-dose effects for humans. All invited speakers agreed to provide their raw data in advance of the meeting to a Statistics Subpanel, which was asked to reevaluate the authors' experimental design, data analysis, and interpretation of experimental results. The purpose of this statistical reevaluation was to provide an independent assessment of the experimental design and data analysis used in each of the studies and to identify key statistical issues relevant to the evaluation and interpretation of the data. This paper presents a summary of the Statistics Subpanel's evaluation. Specific examples are presented to illustrate problems that arose in the experimental design and data analysis of certain studies. The statistical principles and issues that are discussed in this paper are not unique to endocrine disruptor studies and should provide important guidelines regarding appropriate experimental design and statistical analysis for other types of laboratory investigations. [ABSTRACT FROM PUBLISHER]

The article presents a study which examined the level of healthcare use and costs incurred by post-menopausal women in the U.S., focusing attention on cardiovascular disease, osteoporosis, breast cancer, and gynecological cancers. These specific conditions may be labeled postmenopausal health risks in that all may be affected over time by physiological responses to changes in levels of endogens or to levels of exposure to exogenous estrogen, triggered by estrogen receptors in each of these specific body systems. National healthcare survey and discharge data were used to estimate healthcare use by women aged 45 and older. In recent years, women's health has become an increasingly important policy issue. The media and national policymakers including Congress, the National Institutes of Health and other federal agencies, medical, scientific, and women's organizations, have all shown increasing interest in issues related to women's health. The reduction in estrogen production in women after menopause increases risks for osteoporosis and coronary artery disease.

Environmental exposures acting through different mechanisms have been linked with a number of cancers. Perfluoroalkyl chemicals (PFCs) are endocrine disrupting chemicals affecting estrogen homeostasis. We examined the association between PFCs and a group of estrogen related cancers and explored if increased non-occupational exposure was associated with increased odds of developing these cancers. We also explored which of these chemical exposures was more correlated with each cancer. Using data from the National Health and Nutrition Examination Survey (NHANES), we selected participants ≥ 20 years of age. Our outcome variable was presence or absence of breast, prostate, ovarian and uterine cancer (yes/no); our exposure variables were serum PFCs. Logistic regression models were used in investigating the association between PFCs and cancer types and between quartiles of PFCs exposure concentrations and presence or absence of cancer while adjusting for covariates. Discriminant analysis was used to assess the correlation between individual PFCs compounds and individual cancer types. PFCs were associated with increased odds of ovarian cancer; PFOA: 1.02(1.01, 1.02), PFOS: 1.01 (1.012, 1.013), PFHS 1.031 (1.030, 1.033), PFDE: 1.29(1.27, 1.30) and increased odds of breast cancer; PFOA: 1.089(1.089, 1.09), PFOS: 1.011(1.011, 1.011), PFNA: 1.031(1.030, 1.033), PFHS: 1.02 (1.02, 1.02), PFDE: 1.19(1.18, 1.19). PFCs were not associated with increased odds of prostate or uterine cancers. Comparing the odds in quartile 4 to quartile 1 for ovarian cancer, PFOA: 1.77(1.75,1.79), PFOS: 2.25(2.22, 2.28), PFHS: 1.86(1.84, 1.88), PFDE: 2.11(2.09, 2.14). For breast cancer, PFOA: 2.30(2.28, 2.31), PFOS: 1.47(1.46, 1.48), PFNA: 1.04(1.03, 1.05), PFHS:7.07(6.97,7.17), PFDE: 1.38(1.37, 1.39). PFOA was more correlated with breast cancer (0.7) and PFHS was more correlated with ovarian cancer (0.9). PFCs were associated with increased odds of ovarian and breast cancers with a positive dose-response relationship. PFOA was more correlated with breast cancer and PFHS more with ovarian cancer. • Perfluoroalkyl chemicals (PFAS) were detected in the serum of United States residents. • Perfluoroalkyl chemicals were associated with breast cancer. • Perfluoroalkyl chemicals were associated with ovarian cancer. • Relationship of perfluoroalkyl chemicals to breast and ovarian cancer was dose dependent. • Increased odds of uterine and prostate cancers were not associated with perfluoroalkyl chemical exposure. [ABSTRACT FROM AUTHOR]

Background: Non-Hispanic black women (NHB) are diagnosed with triple negative breast cancer (TNBC) more often than other ethnic or racial groups in the United States (US). This study describes regional differences in TNBC incidence among NHB women in the US from 2011 to 2015., Methods: We analyzed data from the United States Cancer Statistics (USCS) that includes incidence data from the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) programs., Results: Compared to the incidence rate for NHB women in the South, rates were significantly lower in the Northeast (22.6 per 100,000), higher in the Midwest (25.5 per 100,000) and similar in the West. These regional differences might be explained by genetic admixture among people with different geographic ancestral origins., Conclusions: Results from this study highlight the need to extend etiological research and evidence-based cancer prevention and control efforts to women at high risk of this disease in order to decrease cancer disparities., (Published by Elsevier Inc.)