Dataset Information

Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients.

ABSTRACT:

Background

Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase I metabolism generates active tamoxifen metabolites, and phase II metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population of premenopausal women.

Methods

We completed a cohort study of 5,959 Danish nonmetastatic premenopausal breast cancer patients, in whom 938 recurrences occurred, and a case-control study of 541 recurrent cases in a cohort of Danish predominantly postmenopausal breast cancer patients, all followed for 10 years. We collected formalin-fixed paraffin-embedded tumor blocks and genotyped 32 variants in 15 genes involved in tamoxifen metabolism or transport. We estimated conventional associations for each variant and used prior information about the tamoxifen metabolic path to evaluate the importance of metabolic and transporter pathways.

Results

No individual variant was notably associated with risk of recurrence in either study population. Both studies showed weak evidence of the importance of phase I metabolism in the clinical response to adjuvant tamoxifen therapy.

Conclusions

Consistent with prior knowledge, our results support the role of phase I metabolic capacity in clinical response to tamoxifen. Nonetheless, no individual variant substantially explained the modest phase I effect on tamoxifen response.

Impact

These results are consistent with guidelines recommending against genotype-guided prescribing of tamoxifen, and for the first time provide evidence supporting these guidelines in premenopausal women.

SUBMITTER: Ahern TP

PROVIDER: S-EPMC7060091 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients.

Ahern Thomas P TP Collin Lindsay J LJ Baurley James W JW Kjærsgaard Anders A Nash Rebecca R Maliniak Maret L ML Damkier Per P Zwick Michael E ME Isett R Benjamin RB Christiansen Peer M PM Ejlertsen Bent B Lauridsen Kristina L KL Christensen Kristina B KB Silliman Rebecca A RA Sørensen Henrik T HT Tramm Trine T Hamilton-Dutoit Stephen S Lash Timothy L TL Cronin-Fenton Deirdre D

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20200113 3

<h4>Background</h4>Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase I metabolism generates active tamoxifen metabolites, and phase II metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population ...[more]

PMID: 31932415

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Project description:BackgroundSerotonin (or 5-Hydroxytryptamine, 5-HT) signals in mammary gland becomes dysregulated in cancer, also contributing to proliferation, metastasis, and angiogenesis. Thus, the discovery of novel compounds targeting serotonin signaling may contribute to tailor new therapeutic strategies usable in combination with endocrine therapies. We have previously synthesized serotoninergic receptor ligands (SER) with high affinity and selectivity towards 5-HT2A and 5-HT2C receptors, the main mediators of mitogenic effect of serotonin in breast cancer (BC). Here, we investigated the effect of 10 SER on viability of MCF7, SKBR3 and MDA-MB231 BC cells and focused on their potential ability to affect Tamoxifen responsiveness in ER+ cells.MethodsCell viability has been assessed by sulforhodamine B assay. Cell cycle has been analyzed by flow cytometry. Gene expression of 5-HT receptors and Connective Tissue Growth Factor (CTGF) has been checked by RT-PCR; mRNA levels of CTGF and ABC transporters have been further measured by qPCR. Protein levels of 5-HT2C receptors have been analyzed by Western blot. All data were statistically analyzed using GraphPad Prism 7.ResultsWe found that treatment with SER for 72 h reduced viability of BC cells. SER were more effective on MCF7 ER+ cells (IC50 range 10.2 μM - 99.2 μM) compared to SKBR3 (IC50 range 43.3 μM - 260 μM) and MDA-MB231 BC cells (IC50 range 91.3 μM - 306 μM). This was paralleled by accumulation of cells in G0/G1 phase of cell cycle. Next, we provided evidence that two ligands, SER79 and SER68, improved the effectiveness of Tamoxifen treatment in MCF7 cells and modulated the expression of CTGF, without affecting viability of MCF10A non-cancer breast epithelial cells. In a cell model of Tamoxifen resistance, SER68 also restored drug effect independently of CTGF.ConclusionsThese results identified serotoninergic receptor ligands potentially usable in combination with Tamoxifen to improve its effectiveness on ER+ BC patients.

Project description:PurposeOverexpression of 14-3-3ζ has been linked to breast cancer recurrence in several studies, including studies assessing its effect on tamoxifen resistance. The study was performed to estimate the effect of 14-3-3ζ and differentiate potential prognostic or predictive utility.MethodsA case-control study, nested in a population of 11,251 females residing on the Jutland Peninsula of Denmark, was performed. Participants were aged 35-69, diagnosed with stage I, II, or III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent breast cancer cases with estrogen receptor-positive disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases with estrogen receptor-negative disease never treated with tamoxifen (ER-/TAM-). We matched cases to controls on ER/TAM status, date of surgery, menopausal status, stage, and county. 14-3-3ζ expression was assessed using immunohistochemistry on tissue microarrays. We computed the odds ratio (OR) associating 14-3-3ζ expression with breast cancer recurrence adjusting for confounding using logistic regression. A quantitative bias analysis was performed to account for bias due to expression assay methods.ResultsAssociations for cytoplasmic and nuclear 14-3-3ζ staining above the 50th percentile were near null in both ER+/TAM+ and ER-/TAM- patients. When examining combined 14-3-3ζ staining, the association increased in the ER+/TAM+ group (adjusted OR 1.44, 95% confidence interval (CI) 1.05, 1.99). A nearly twofold increase in odds of recurrence was observed in above the 75th percentile staining of combined 14-3-3ζ, both for ER+/TAM+ patients (adjusted OR 1.93, 95% CI 1.15, 3.24) and ER-/TAM- patients (adjusted OR 1.93, 95% CI 1.03, 3.62), indicating potential prognostic utility.ConclusionEvidence is lacking to conclude that 14-3-3ζ is a useful marker of tamoxifen resistance; however, 14-3-3ζ expression is a potentially useful prognostic marker of breast cancer recurrence. Independent utility beyond established prognostic markers needs to be determined.

Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.

Dataset Information

Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients.

Background

Methods

Results

Conclusions

Impact

Publications

Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients.

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