Advertisement

The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies

  • Berry Button
  • Sarah Croessmann
  • David Chu
  • D. Marc Rosen
  • Daniel J. Zabransky
  • W. Brian Dalton
  • Karen Cravero
  • Kelly Kyker-Snowman
  • Ian Waters
  • Swathi Karthikeyan
  • Eric S. Christenson
  • Josh Donaldson
  • Tasha Hunter
  • Lauren Dennison
  • Cody Ramin
  • Betty May
  • Richard Roden
  • Dana Petry
  • Deborah K. Armstrong
  • Kala Visvanathan
  • Ben Ho ParkEmail author
Preclinical study
  • 83 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Breast cancer ESR1 Endocrine resistance 

Notes

Acknowledgements

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.

Funding

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.

Ethical approval

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.

Informed consent

All study participants provided informed consent under an IRB-approved protocol.

Supplementary material

10549_2018_5087_MOESM1_ESM.pdf (298 kb)
Supplementary material 1 (PDF 297 KB)

References

  1. 1.
    Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276(13):9817–9824CrossRefGoogle Scholar
  2. 2.
    Migliaccio A, Piccolo D, Castoria G, Di Domenico M, Bilancio A, Lombardi M, Gong W, Beato M, Auricchio F (1998) Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J 17(7):2008–2018CrossRefGoogle Scholar
  3. 3.
    McKenna NJ, Nawaz Z, Tsai SY, Tsai MJ, O’Malley BW (1998) Distinct steady-state nuclear receptor coregulator complexes exist in vivo. Proc Natl Acad Sci USA 95(20):11697–11702CrossRefGoogle Scholar
  4. 4.
    Duplessis TT, Williams CC, Hill SM, Rowan BG (2011) Phosphorylation of Estrogen Receptor alpha at serine 118 directs recruitment of promoter complexes and gene-specific transcription. Endocrinology 152(6):2517–2526CrossRefGoogle Scholar
  5. 5.
    Anbalagan M, Rowan BG (2015) Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol Cell Endocrinol 418:264–272CrossRefGoogle Scholar
  6. 6.
    Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y, Skaar TC, Gomez B, O’Brien K, Wang Y et al (2003) Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene 22(47):7316–7339CrossRefGoogle Scholar
  7. 7.
    Abukhdeir AM, Vitolo MI, Argani P, De Marzo AM, Karakas B, Konishi H, Gustin JP, Lauring J, Garay JP, Pendleton C et al (2008) Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci USA 105(1):288–293CrossRefGoogle Scholar
  8. 8.
    Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451CrossRefGoogle Scholar
  9. 9.
    Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439–1445CrossRefGoogle Scholar
  10. 10.
    Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gomez H et al (2014) Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20(7):1757–1767CrossRefGoogle Scholar
  11. 11.
    Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C et al (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4(6):1116–1130CrossRefGoogle Scholar
  12. 12.
    Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, Yelensky R, Brown M, Miller VA, Sarid D et al (2013) D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res 73(23):6856–6864CrossRefGoogle Scholar
  13. 13.
    Parsons HA, Beaver JA, Cimino-Mathews A, Ali SM, Axilbund J, Chu D, Connolly RM, Cochran RL, Croessmann S, Clark TA et al (2017) Individualized molecular analyses guide efforts (IMAGE): a prospective study of molecular profiling of tissue and blood in metastatic triple-negative breast cancer. Clin Cancer Res 23(2):379–386CrossRefGoogle Scholar
  14. 14.
    Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA, Pritchard KI, Campone M, Noguchi S, Perez AT, Deleu I et al (2016) Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J clin Oncol 34(5):419–426CrossRefGoogle Scholar
  15. 15.
    Sfakianos JP, Cha EK, Iyer G, Scott SN, Zabor EC, Shah RH, Ren Q, Bagrodia A, Kim PH, Hakimi AA et al (2015) Genomic characterization of upper tract urothelial carcinoma. Euro Urol 68(6):970–977CrossRefGoogle Scholar
  16. 16.
    Rebai M, Rebai A (2016) In silico characterization of functional SNP within the oestrogen receptor gene. J Genet 95(4):865–874CrossRefGoogle Scholar
  17. 17.
    Bunone G, Briand PA, Miksicek RJ, Picard D (1996) Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15(9):2174–2183CrossRefGoogle Scholar
  18. 18.
    Chen D, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly JM et al (2002) Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene 21(32):4921–4931CrossRefGoogle Scholar
  19. 19.
    Chen M, Cui YK, Huang WH, Man K, Zhang GJ (2013) Phosphorylation of estrogen receptor alpha at serine 118 is correlated with breast cancer resistance to tamoxifen. Oncol Lett 6(1):118–124CrossRefGoogle Scholar
  20. 20.
    Cheng J, Zhang C, Shapiro DJ (2007) A functional serine 118 phosphorylation site in estrogen receptor-alpha is required for down-regulation of gene expression by 17beta-estradiol and 4-hydroxytamoxifen. Endocrinology 148(10):4634–4641CrossRefGoogle Scholar
  21. 21.
    Zabransky DJ, Yankaskas CL, Cochran RL, Wong HY, Croessmann S, Chu D, Kavuri SM, Red Brewer M, Rosen DM, Dalton WB et al (2015) HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proc Natl Acad Sci USA 112(45):E6205–E6214CrossRefGoogle Scholar
  22. 22.
    Abukhdeir AM, Blair BG, Brenner K, Karakas B, Konishi H, Lim J, Sahasranaman V, Huang Y, Keen J, Davidson N et al (2006) Physiologic estrogen receptor alpha signaling in non-tumorigenic human mammary epithelial cells. Breast Cancer Res Treat 99(1):23–33CrossRefGoogle Scholar
  23. 23.
    Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W, Nardone A, Xiao T, Li W, Qiu X, Buchwalter G et al (2018) Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell 33(2):173–186 e175CrossRefGoogle Scholar
  24. 24.
    Tian D, Solodin NM, Rajbhandari P, Bjorklund K, Alarid ET, Kreeger PK (2015) A kinetic model identifies phosphorylated estrogen receptor-alpha (ERalpha) as a critical regulator of ERalpha dynamics in breast cancer. FASEB J 29(5):2022–2031CrossRefGoogle Scholar
  25. 25.
    Murphy LC, Weitsman GE, Skliris GP, Teh EM, Li L, Peng B, Davie JR, Ung K, Niu YL, Troup S et al (2006) Potential role of estrogen receptor alpha (ERalpha) phosphorylated at Serine118 in human breast cancer in vivo. J Steroid Biochem Mol Biol 102(1–5):139–146CrossRefGoogle Scholar
  26. 26.
    Huderson BP, Duplessis TT, Williams CC, Seger HC, Marsden CG, Pouey KJ, Hill SM, Rowan BG (2012) Stable inhibition of specific estrogen receptor alpha (ERalpha) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells. Endocrinology 153(9):4144–4159CrossRefGoogle Scholar
  27. 27.
    Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, Konishi Y et al (2009) Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci USA 106(8):2835–2840CrossRefGoogle Scholar
  28. 28.
    Dean L (2012) Tamoxifen therapy and CYP2D6 genotype. In: Pratt V, McLeod H, Rubinstein W, Dean L, Kattman B, Malheiro A (ed) Medical genetics summaries. National Center for Biotechnology Information, Bethesda, MDGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Berry Button
    • 1
  • Sarah Croessmann
    • 2
  • David Chu
    • 1
  • D. Marc Rosen
    • 1
  • Daniel J. Zabransky
    • 1
  • W. Brian Dalton
    • 1
  • Karen Cravero
    • 1
  • Kelly Kyker-Snowman
    • 1
  • Ian Waters
    • 1
  • Swathi Karthikeyan
    • 1
  • Eric S. Christenson
    • 1
  • Josh Donaldson
    • 1
  • Tasha Hunter
    • 1
  • Lauren Dennison
    • 1
  • Cody Ramin
    • 4
  • Betty May
    • 4
  • Richard Roden
    • 4
  • Dana Petry
    • 1
  • Deborah K. Armstrong
    • 1
  • Kala Visvanathan
    • 1
    • 4
  • Ben Ho Park
    • 1
    • 2
    • 3
    Email author return OK on get
  1. 1.The Sidney Kimmel Comprehensive Cancer CenterThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Vanderbilt Ingram Cancer CenterVanderbilt Universtiy Medical CenterNashvilleUSA
  3. 3.Department of Chemical and Biomolecular Engineering, The Whiting School of EngineeringThe Johns Hopkins UniversityBaltimoreUSA
  4. 4.The Johns Hopkins University Bloomberg School of Public HealthBaltimoreUSA

Personalised recommendations