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Purpose:Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC.Experimental Design:Mutant p53–associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines. Mutant p53–dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L; FaDu, carrying p53R248L; and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC–dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network–based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and patient-derived xenografts (PDX) models.Results:We identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in PDX and cell lines of HNSCC treated with the PI3Kα-selective inhibitor BYL719 (alpelisib) the downregulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53, and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53, or YAP potentiates the effectiveness of BYL719 treatment.Conclusions:Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.

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Background: miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development.Methods: Using a case–control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years.Results: The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation.Conclusions: These observations and the prospective design of our study lend support to the hypothesis that downregulation of specific miRNAs constitutes an early event in cancer development. This finding might be used for breast cancer prevention.Impact: The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact on breast cancer prevention and early detection. Cancer Epidemiol Biomarkers Prev; 23(11); 2471–81. ©2014 AACR.

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Supplementary Table 1 - miR-125a-5p expression across different databases; Supplementary Table 2 - miR-99b expression across different databases; Supplementary Table 3 - miR-199a-5p expression across different databases; Supplementary Table 4 - miR-199b-5p expression across different databases; Supplementary Table 5 - miR-892b expression across different databases; Supplementary Table 6 - miR-141 expression across different databases; Supplementary Table 7 - miR-582-5p expression across different databases; Supplementary Table 8 - miR-138 expression across different databases; Supplementary Table 9 - miR-181c* expression across different databases; Supplementary Table 10 - miR-28-3p expression across different databases; Supplementary Table 11 - miR-1288 expression across different databases; Supplementary Table 12 - miR-224 expression across different databases; Supplementary Table 13 - miR-520a-3p expression across different databases; Supplementary Table 14 - miR-223 expression across different databases; Supplementary Table 15 - miR-539 expression across different databases; Supplementary Table 16 - miR-542-5p expression across different databases; Supplementary Table 17 - miR-122* expression across different databases; Supplementary Table 18 - miR-920 expression across different databases.

Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D). Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures. Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85–1.03; I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44–0.70; I2 = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots. Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases. Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627–35. ©2018 AACR.

Background: Endogenous sex hormone levels have been associated with increased breast cancer risk in postmenopausal women in several prospective studies. However, it remains unclear to what extent serum hormone-breast cancer associations differ with receptor status. Methods: Associations between serum sex hormone levels and breast cancer risk were assessed in a nested case-control study on postmenopausal women of the ORDET cohort. After a median follow-up of 13.5 years, 165 women developed breast cancer. Relative risks of developing breast cancer were estimated by conditional logistic regression. Results: Total and free testosterone levels were directly associated with breast cancer risk [relative risk, 3.28 (95% confidence interval, 1.93-5.55) and 2.86 (95% confidence interval, 1.66-4.94), respectively, for highest versus lowest quartile]. When relations between hormone level and risk of breast cancer expressing various receptor combinations were assessed, high total testosterone was significantly associated with increased risk of estrogen receptor–positive cancers, irrespective of progesterone receptor status. High total testosterone was also associated with increased risk of both human epidermal growth factor receptor 2 (HER2)–negative (HER2−) and HER2+ cancers. High estradiol tended to be associated with increased risk of HER2− cancer and inversely associated with HER2+ cancer, with significant (P = 0.027) heterogeneity between HER2+ and HER2− cancers. However, there were relatively few HER2+ cases. Conclusions: This study provides further evidence that high levels of circulating testosterone increase the risk of developing breast cancer in postmenopausal women. The cancers that develop are mainly estrogen receptor positive. Although HER2+ and HER2− breast cancers were both associated with high total testosterone, they showed opposing associations with estrogen. (Cancer Epidemiol Biomarkers Prev 2009;18(1):169–76)

Catalase, a ubiquitous heme enzyme, catalyzes conversion of hydrogen peroxide to water and molecular oxygen, protecting cells from oxidative stress. A C/T polymorphism in the promoter region of the CAT gene (rs1001179) affects transcriptional activity and RBC catalase levels. Oxidative stress may explain the observed increased postmenopausal breast cancer risk associated with hormone replacement therapy (HRT). We examined CAT genotype, HRT, and postmenopausal breast cancer risk in the Western New York Exposures and Breast Cancer case-control study. Cases (n = 616) were women with primary, incident, pathologically confirmed breast cancer. Randomly selected controls (n = 1,082) were frequency matched to cases on age and race. Genotype was assayed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for potential confounders. CAT genotype alone was not associated with breast cancer risk. Ever use of HRT was associated with increased risk (OR, 1.39; 95% CI, 1.11-1.75). The increase with ever use was more pronounced among those with variant CT or TT CAT genotype (OR, 1.88; 95% CI, 1.29-2.75) than among those with CC (OR, 1.15; 95% CI, 0.86-1.54). Similarly, risk associated with ≥5 years of HRT use was greater among those with at least one variant T allele (OR, 2.32; 95% CI, 1.50-3.59). Increased risk was limited to estrogen receptor–positive tumors. Our findings suggest that CAT genotype modifies the effect of HRT use on breast cancer risk and that HRT may affect risk by affecting oxidative stress. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1082–7)

Specific fatty acids may have differential effects on breast cancer etiology. Animal studies have suggested that conjugated linoleic acids (CLA), a group of fatty acids found predominantly in dairy products and the meat of ruminants, have potent anticarcinogenic properties. We examined breast cancer risk and dietary CLA intake among 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases by age, race, and county of residence. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. We examined risk with intake of total CLAs and the 9c,11t-18:2 isomer of CLA (9,11 CLA). Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression, adjusting for age, the residual of fat adjusted for energy, and other breast cancer risk factors. No association was observed between intakes of total CLA or 9,11 CLA and overall risk of premenopausal or postmenopausal breast cancer. We observed little association between CLA intakes and risk of estrogen receptor (ER)–negative or ER-positive tumors, although, compared with premenopausal women in the lowest quartile of 9,11 CLA intake, those in the highest quartile had a marginally significant reduction in risk of having an ER-negative tumor (odds ratio, 0.40; 95% confidence interval, 0.16–1.01). Our findings suggest that, although CLA intake was not related to overall breast cancer risk, there may be associations with tumor biology at least among premenopausal women.

Estrogens play important roles in the pathophysiology of breast tumors and are recognized causal factors in the etiology of breast cancer. Parent estrogens (estrone and estradiol) can be hydroxylated at the 2, 4, or 16 position of the steroid ring, resulting in metabolites with different biological activity and availability. Estrogen metabolism shows great inter-individual variation, is modifiable, and may contribute to differences among women at risk of breast cancer. We conducted a cross-sectional study to investigate whether urinary estrogens and estrogen metabolites (jointly referred to as EM) are associated with mammographic density (MD), the strongest predictor of sporadic breast cancer risk among women apart from age. Methods: Postmenopausal women without breast cancer, aged 48–82 y, and reporting no current use of exogenous hormones were recruited and interviewed at a mammography clinic in Western NY in 2005. Concentrations of 15 EM were measured in first morning urine samples from 195 participants using liquid chromatography-tandem mass spectrometry. MD (%) was measured using computer-assisted analyses of digitized films. Linear models were used to assess associations of log-transformed EM concentrations and ratios with MD while adjusting for age, body mass index (BMI, kg/m2), and history of combination menopausal hormone therapy. We assessed effect modification by these factors and by years since menopause. Results: The median age of participants was 58, and median time since menopause was 8 years; 35% of participants were obese (BMI ≥30), and 33% had previously used combination menopausal hormones. Among all participants, urinary concentrations of parent estrogens were not associated with MD while some individual 2-pathway and 4-pathway EM had significant inverse associations with MD. Associations between EM profiles and MD were modified by years since menopause (≤8 or >8 y) and by obesity. Among women with a recent menopause, MD was positively associated with parent estrogens (p=0.02), and inversely associated with 2- and 4-hydroxylation pathway EM (p=0.03 and 0.02); these associations were not observed in women with a more distant menopause (pinteraction=0.02, 0.18, 0.16, respectively). Similarly, parent estrogens were directly associated with MD (p=0.003) among women who were obese but not among thinner counterparts (pinteraction=0.08). Conclusion: This is the first study to examine the relations between 15 EM and MD in postmenopausal women. EM profiles were most strongly associated with MD in subgroups with higher estrogen levels including obese women and those with a more recent menopause. In these groups, more extensive 2- and 4-hydroxylation of parent estrogens was associated with reduced MD. This pattern of metabolism may influence MD by facilitating clearance of estrogens from breast tissues. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A8.

Breast cancer (BC) is the most common malignancy in women; worldwide, it is the second most common type of cancer after lung cancer and the fifth most common cause of cancer death. BC progresses as a multi-step process encompassing progressive changes. Although the majority of concepts related to morphologically-defined breast precursor lesions remain valid, molecular genetics and tumor phenotypic characterization have changed the way that the BC multi-step model is viewed. More recently, profiling BC using expression array technology has unravelled a novel molecular taxonomy which classifies BC in three main groups: Luminal, Basal-like and HER2, thereby further extending our knowledge regarding BC biology. microRNA is a new class of small molecules that has been linked to the regulation of proliferation, differentiation, apoptosis and even exocytosis. Accumulating evidence indicates that miRNAs are critical in the control of cell proliferation and survival. In particular, miRNAs show altered expression in cancers, in relation to that shown in normal tissue, which distinguishes cancers arising in different physiological sites. Some miRNAs exhibit differential expression levels in cancer and have demonstrated capability to affect cellular transformation, carcinogenesis and metastasis by acting either as oncogenes or tumor suppressors. Although microRNAs were discovered in humans a mere eight years ago, a host of promising potential applications in the diagnosis, prognoses and therapy of cancer is emerging at a rapid pace. Indeed, specific miRNA expression signatures could have a prognostic value, indicating that miRNAs are determinants of clinical aggressiveness. In this context, newly developed technology like microRNA profiling could have not only the potential to classify tumors but also to predict patient outcome with a high accuracy. In our study we analyzed the three main groups of breast cancer (BC) subtypes: Luminal, Basal-like and HER2. Two biopsies, from the tumor itself and from the peri-tumoral area, were obtained from each patient included in the study. In addition, biopsies from some healthy tissues (reductive mammoplasty) were also analyzed. We extracted RNA using TriZOL reagent and then checked, with the Agilent bioanalyzer, the quality of the samples. We performed the hybridization on Human miRNA Microarray from Agilent that contained probes for 723 human and 76 human viral microRNAs from the Sanger database v.10.1. The bioinformatic analysis revealed distinct groups of miRNAs that were selectively modulated by comparing tumor and peritumoral samples. Experimental work aimed at dissecting the functional role of microRNAs in breast cancer model is in progress. We believe that our work could contribute to a better understanding of the oncogenic potential of a specific subset of miRs and in general help to clarify the role of these microRNAs in the tumorigenic process of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3010.

To the Editor: We read with great interest the article by Cazzaniga et al. ([1][1]) on the potential use of the insulin sensitizing agent metformin for therapeutic and chemopreventive purposes in breast cancer. We found that the safety profile of metformin was inadequately elicited and poorly