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, William Dalton, Karen Cravero, Kelly Kyker-Snowman, Ian Waters, Swathi Karthikeyan, Eric S. Christenson, Josh Donaldson, Tasha Hunter, Lauren Dennison, Cody Ramin, Betty May, Richard S Roden, Dana Petry, Deborah Kay Armstrong, Kala VisvanathanBen Ho Park

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Estrogen Receptor alpha
Breast Neoplasms
Incidence
Therapeutics
Mediator Complex
Hormones
MAP Kinase Signaling System
Tamoxifen
Serine
Registries
Estrogens
Breast
Epithelial Cells
Phosphorylation
Databases
Ligands
Cell Line

Keywords

  • Breast cancer
  • Endocrine resistance
  • ESR1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies. / Button, Berry; Croessmann, Sarah; Chu, David; Rosen, D. Marc; Zabransky, Daniel J.; Dalton, William; Cravero, Karen; Kyker-Snowman, Kelly; Waters, Ian; Karthikeyan, Swathi; Christenson, Eric S.; Donaldson, Josh; Hunter, Tasha; Dennison, Lauren; Ramin, Cody; May, Betty; Roden, Richard S; Petry, Dana; Armstrong, Deborah Kay; Visvanathan, Kala; Park, Ben Ho.

In: Breast Cancer Research and Treatment, 01.01.2018.

Research output: Contribution to journalArticle

Button, B, Croessmann, S, Chu, D, Rosen, DM, Zabransky, DJ, Dalton, W, Cravero, K, Kyker-Snowman, K, Waters, I, Karthikeyan, S, Christenson, ES, Donaldson, J, Hunter, T, Dennison, L, Ramin, C, May, B, Roden, RS, Petry, D, Armstrong, DK, Visvanathan, K & Park, BH 2018, 'The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies', Breast Cancer Research and Treatment. https://doi.org/10.1007/s10549-018-05087-7
Button, Berry ; Croessmann, Sarah ; Chu, David ; Rosen, D. Marc ; Zabransky, Daniel J. ; Dalton, William ; Cravero, Karen ; Kyker-Snowman, Kelly ; Waters, Ian ; Karthikeyan, Swathi ; Christenson, Eric S. ; Donaldson, Josh ; Hunter, Tasha ; Dennison, Lauren ; Ramin, Cody ; May, Betty ; Roden, Richard S ; Petry, Dana ; Armstrong, Deborah Kay ; Visvanathan, Kala ; Park, Ben Ho. / The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies. In: Breast Cancer Research and Treatment. 2018.
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AU - Button, Berry

AU - Croessmann, Sarah

AU - Chu, David

AU - Rosen, D. Marc

AU - Zabransky, Daniel J.

AU - Dalton, William

AU - Cravero, Karen

AU - Kyker-Snowman, Kelly

AU - Waters, Ian

AU - Karthikeyan, Swathi

AU - Christenson, Eric S.

AU - Donaldson, Josh

AU - Hunter, Tasha

AU - Dennison, Lauren

AU - Ramin, Cody

AU - May, Betty

AU - Roden, Richard S

AU - Petry, Dana

AU - Armstrong, Deborah Kay

AU - Visvanathan, Kala

AU - Park, Ben Ho

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AB - 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.

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