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Tamoxifen (TAM) is an antiestrogenic agent used for adjuvant treatment in estrogen receptor‐positive breast cancers in the pre/post‐menopausal period. This study, it was aimed to determine the effect of olive oil extract of propolis (OEP) on short and long‐term administration of TAM in rats. Wistar albino rats were divided into groups with eight animals in each. Groups: control, OEP, TAM, and OEP + TAM. At the end of the experiment, oxidative stress tests were performed with Enzyme‐Linked ImmunoSorbent Assay (ELISA) on blood and tissue samples (liver, kidney, and ovary) taken from rats. After single‐dose TAM administration, there was a significant increase in red blood cell, hematocrit, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration levels compared to the control group, a decrease in low‐density lipoprotein (LDL) value, a significant increase in liver enzymes and fasting glucose values was detected compared with the control and propolis groups. A normalizing effect was observed in the group given OEP and TAM combined. The increase in Malondialdehyde (MDA) and the decrease in enzyme activities in tissues are also noteworthy. Propolis application reduced the tissue damage caused by TAM. In addition, improved cytokine levels, which increased with TAM administration. It has been concluded that OEP can be given in supportive treatment, as it improves hematological and antioxidant parameters in TAM treatment. [ABSTRACT FROM AUTHOR]

Abstract Background The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor-related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2-related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown. Methods Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro. Results We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown. Conclusion We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated.

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA , BRIP1 , and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2 , CKS2 , GINS2 , PCNA , MCM5 , and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found. [ABSTRACT FROM AUTHOR]

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2016 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2016 article‐contains‐esm Yes article‐numbering‐style Unnumbered article‐registration‐date‐year 2016 article‐registration‐date‐month 3 article‐registration‐date‐day 4 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2016_Article_90.pdf pdf‐type Typeset target‐type OnlinePDF issue‐type Regular article‐type OriginalPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection Medicine open‐access true --> Background: Tamoxifen is used in endocrine treatment of breast cancer to inhibit estrogen signaling. A set of stratified ER‐positive and ER‐negative tumor sections was subjected to manual deposition of tamoxifen solution in order to investigate its spatial distribution upon exposure to interaction within thin tissue sections. Methods: The localization of tamoxifen in tumor sections was assessed by matrix assisted laser deposition/ionization mass spectrometry imaging. The images of extracted ion maps were analyzed for comparison of signal intensity distributions. Results: The precursor ion of tamoxifen (m/z 372.233) displayed heterogeneous signal intensity distributions in histological compartments of tumor tissue sections. The levels of tamoxifen in tumor cells compared with stroma were higher in ER‐positive tissues, whereas ER‐negative tissue sections showed lower signal intensities in tumor cells. Conclusions: The experimental model was successfully applied on frozen tumor samples allowing for differentiation between ER groups based on distribution of tamoxifen. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe health-related quality of life (HRQoL) and productivity in Dutch breast cancer patients treated with tamoxifen in an adjuvant setting. Patients who started treatment with a standard dose of tamoxifen and who gave written informed consent, were eligible for participation in this trial. A total of 145 patients were asked to complete a survey at 3 months (T1) and 6 months (T2) after initiation of tamoxifen. HRQoL was measured by the EQ-5D-5L and the FACT-B questionnaire, and productivity by using the iMTA Productivity Costs Questionnaire. At 3 months 137 (95%) and at 6 months 133 (92%) patients responded to the surveys. EQ-5D-5 L utility values for T1 and T2 were 0.81 ± 0.17 and 0.81 ± 0.18, respectively. FACT-B scores for T1 and T2 were 109 ± 17.9 and 108 ± 20.0, respectively. No differences in both EQ-5D-5 L utility and FACT-B scores were found between T1 and T2 (p > 0.05). Age and employment status were statistically significantly associated with FACT-B scores (p = 0.04 and p = 0.03, respectively), indicating that younger and unemployed respondents had lower FACT-B scores. Importantly, both short-term and long-term productivity improved during the first six months of tamoxifen treatment (p < 0.05). Here, short-term productivity losses (consisting of absenteeism, presenteeism and unpaid work) for T1 and T2 were estimated at € 855,- and € 396,-, respectively. Long-term productivity losses (consisting of absenteeism) for T1 and T2 were estimated at € 2876,- and € 1104,-, respectively. In conclusion, this study presents HRQoL scores using different instruments and detailed loss of productivity estimates for breast cancer patients treated with adjuvant endocrine therapy. The results presented here can be used to inform input parameters in health economic evaluations of interventions for patients with breast cancer in the Netherlands and other Western countries and ultimately support decision making. [Display omitted] • Health economic models require input parameters to describe the patient population evaluated. • The EQ-5D-5 L and FACT-B and productivity were assessed in tamoxifen-treated breast cancer patients. • Younger and employed patients had overall better quality of life. • Productivity of patients improved during the first 6 months of treatment with tamoxifen. [ABSTRACT FROM AUTHOR]

Objective: Genistein is a phytoestrogen with in vitro anticancerogenic activity. We examined in vitro the effects of genistein alone, or in combination with estradiol and tamoxifen, on the growth of human dysplastic and malignant epithelial breast cell lines. Methods: Dysplastic breast cell lines (MCF-10A1, MCF-ANeoT, MCF-T63B) and cell lines of breast cancer (MCF-7, MDA-231, MDA-435) were cultured as monolayers in RPMI 1640 medium supplemented with 10% fetal bovine serum, and l-glutamine. After preincubation of 20 h, genistein (1, 2.5, 5, 7.5 and 10 μg/ml) alone or in combination with estrogen or tamoxifen was added to the cultured cells. The cells were treated continuously for 72 h and then the growth rate was assessed colorimetrically. Stepwise multiple linear regression analysis was used to evaluate the effect of genistein, tamoxifen, and estradiol on cell proliferation. Results: Genistein had a significant (dose-dependent) inhibitory effect on the proliferation of both dysplastic (P<0.0001) and malignant (P<0.0001) cells. The growth inhibition was significantly higher P<0.0001 in dysplastic cells compared to the cancer cells. Addition of tamoxifen to genistein further inhibited the proliferation of both cell types, reflecting a synergistic antiproliferative effect on dysplastic cells P<0.0001 and an additive growth inhibition effect P<0.0003 on malignant cells. Estradiol significantly (P=0.005) stimulated the growth of dysplastic cell lines while a significant (P=0.003) antiproliferative effect on growth of the malignant cells was observed. The concentration of estrogen receptor (ER) had no significant effect on growth rates and did not modulate the effects of genistein or tamoxifen. Conclusions: Genistein (1–10 μg/ml) inhibits the growth of dysplastic and malignant epithelial breast cancer cells in vitro and the addition of tamoxifen (10−6, 10−7 M) has a synergistic/additive inhibitory effect. These effects are not modulated by the presence of ER. [Copyright &y& Elsevier]

Simple Summary: Tamoxifen is an important adjuvant endocrine therapy in estrogen receptor (ER)-positive breast cancer patients. It is mainly catalyzed by the enzyme CYP2D6 into the most active metabolite endoxifen. Genetic variation in the CYP2D6 gene influences endoxifen formation and thereby potentially therapy outcome. However, the association between CYP2D6 genotype and clinical outcome on tamoxifen is still under debate, as contradictory outcomes have been published. This review describes the latest insights in both CYP2D6 genotype and endoxifen concentrations, as well CYP2D6 genotype and clinical outcome, from 2018 to 2020. Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate. [ABSTRACT FROM AUTHOR]

Aim: To establish downregulated biomarkers for cross-resistance for radiotherapy (RT) in tamoxifen (TAM)-resistant breast cancer cells. Materials & methods: RNA sequencing was performed on TAM and RT-resistant breast cancer cells. Breast cancer patient cohorts were queried in silico for associations between genes of interest and outcome after TAM treatment or irradiation. Results:  20 genes showed decreased expression in both TAM-resistant and RT-resistant breast cancer cells. Only matrix Gla protein in the primary tumor was associated with outcome after TAM treatment or RT in breast cancer patients. Conclusion: Matrix Gla protein is a biomarker for therapy sensitivity in breast cancer.