The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies
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Estrogen receptor-alpha (ER) is a therapeutic target of ER-positive (ER+) breast cancers. Although ER signaling is complex, many mediators of this pathway have been identified. Specifically, phosphorylation of ER at serine 118 affects responses to estrogen and therapeutic ligands and has been correlated with clinical outcomes in ER+ breast cancer patients. We hypothesized that a newly described germline variant (S118P) at this residue would drive cellular changes consistent with breast cancer development and/or hormone resistance.
Isogenic human breast epithelial cell line models harboring ER S118P were developed via genome editing and characterized to determine the functional effects of this variant. We also examined the frequency of ER S118P in a case–control study (N = 536) of women with and without breast cancer with a familial risk.
In heterozygous knock-in models, the S118P variant demonstrated no significant change in proliferation, migration, MAP Kinase pathway signaling, or response to the endocrine therapies tamoxifen and fulvestrant. Further, there was no difference in the prevalence of S118P between women with and without cancer relative to population registry databases.
This study suggests that the ER S118P variant does not affect risk for breast cancer or hormone therapy resistance. Germline screening and modification of treatments for patients harboring this variant are likely not warranted.
KeywordsBreast cancer ESR1 Endocrine resistance
The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract Nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). The authors thank the staff and participants of the ARIC study for their important contributions. The authors would like to thank the BOSS cohort participants. Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed.
This work was supported by The Komen Foundation (B.H.P.), NIH CA214494 (B.H.P.), NIH CA088843 and CA194024 (K.C. and B.H.P.), GM008752 (B.B.), NIH CA009314 (CR), and NIH CA009071 (W.B.D., E.C., and J.D.). We would also like to thank and acknowledge the support of the Commonwealth Foundation, the Breast Cancer Research Foundation, The Canney Foundation, the M&E Foundation, Avon Breast Cancer Research Program Network, and the Johns Hopkins Fetting Fund. None of the authors have a financial relationship with the organizations that sponsored the research.
Compliance with ethical standards
Conflict of interest
B.H.P. has ownership interest and is a paid member of the scientific advisory board of Loxo Oncology and is a paid consultant for Foundation Medicine, Inc, Jackson Labs, Roche, Casdin Capital and H3 Biomedicine. Under separate licensing agreements between Horizon Discovery, LTD and The Johns Hopkins University, B.H.P. is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. No other authors declare potential conflicts of interest.
All animal experiments were performed in accordance with institutional and The National Institutes of Health Guide for the Care and Use of Laboratory Animals guidelines. All studies were performed in compliance with institutional ethical standards.
All study participants provided informed consent under an IRB-approved protocol.
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