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.
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 cancerpatients. 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 humanbreast 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.
Entities:
Keywords:
Breast cancer; ESR1; Endocrine resistance
Authors: B P Huderson; T T Duplessis; C C Williams; H C Seger; C G Marsden; K J Pouey; S M Hill; B G Rowan Journal: Endocrinology Date: 2012-06-25 Impact factor: 4.736
Authors: Leigh C Murphy; G E Weitsman; G P Skliris; E M Teh; Lin Li; B Peng; J R Davie; K Ung; Y-L Niu; S Troup; L Tomes; P H Watson Journal: J Steroid Biochem Mol Biol Date: 2006-11-07 Impact factor: 4.292
Authors: Abde M Abukhdeir; Michele I Vitolo; Pedram Argani; Angelo M De Marzo; Bedri Karakas; Hiroyuki Konishi; John P Gustin; Josh Lauring; Joseph P Garay; Courtney Pendleton; Yuko Konishi; Brian G Blair; Keith Brenner; Elizabeth Garrett-Mayer; Hetty Carraway; Kurtis E Bachman; Ben Ho Park Journal: Proc Natl Acad Sci U S A Date: 2007-12-27 Impact factor: 11.205
Authors: Robert Clarke; Minetta C Liu; Kerrie B Bouker; Zhiping Gu; Richard Y Lee; Yuelin Zhu; Todd C Skaar; Bianca Gomez; Kerry O'Brien; Yue Wang; Leena A Hilakivi-Clarke Journal: Oncogene Date: 2003-10-20 Impact factor: 9.867
Authors: Abde M Abukhdeir; Brian G Blair; Keith Brenner; Bedri Karakas; Hiroyuki Konishi; Joselin Lim; Vanita Sahasranaman; Yi Huang; Judith Keen; Nancy Davidson; Michele I Vitolo; Kurtis E Bachman; Ben Ho Park Journal: Breast Cancer Res Treat Date: 2006-03-16 Impact factor: 4.872
Authors: John P Gustin; Bedri Karakas; Michele B Weiss; Abde M Abukhdeir; Josh Lauring; Joseph P Garay; David Cosgrove; Akina Tamaki; Hiroyuki Konishi; Yuko Konishi; Morassa Mohseni; Grace Wang; D Marc Rosen; Samuel R Denmeade; Michaela J Higgins; Michele I Vitolo; Kurtis E Bachman; Ben Ho Park Journal: Proc Natl Acad Sci U S A Date: 2009-02-05 Impact factor: 11.205
Authors: Sarah A Jeffreys; Branka Powter; Bavanthi Balakrishnar; Kelly Mok; Patsy Soon; André Franken; Hans Neubauer; Paul de Souza; Therese M Becker Journal: Cells Date: 2020-09-11 Impact factor: 6.600