Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes

Shanhang Jia, Mark T. Miedel, Marilyn Ngo, Ryan Hessenius, Ning Chen, Peilu Wang, Amir Bahreini, Zheqi Li, Zhijie Ding, Tong Ying Shun, Daniel M. Zuckerman, D. Lansing Taylor, Shannon L. Puhalla, Adrian V. Lee, Steffi Oesterreich, Andrew M. Stern

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Objective: Twenty to fifty percent of estrogen receptor-positive (ER+) metastatic breast cancers express mutations within the ER ligand-binding domain. While most studies focused on the constitutive ER signaling activity commonly engendered by these mutations selected during estrogen deprivation therapy, our study was aimed at investigating distinctive phenotypes conferred by different mutations within this class. Methods: We examined the two most prevalent mutations, D538G and Y537S, employing corroborative genome-edited and lentiviral-transduced ER+ T47D cell models. We used a luciferase-based reporter and endogenous phospho-ER immunoblot analysis to characterize the estrogen response of ER mutants and determined their resistance to known ER antagonists. Results: Consistent with their selection during estrogen deprivation therapy, these mutants conferred constitutive ER activity. While Y537S mutants showed no estrogen dependence, D538G mutants demonstrated an enhanced estrogen-dependent response. Both mutations conferred resistance to ER antagonists that was overcome at higher doses acting specifically through their ER target. Conclusions: These observations provide a tenable hypothesis for how D538G ESR1-expressing clones can contribute to shorter progression-free survival observed in the exemestane arm of the BOLERO-2 study. Thus, in those patients with dominant D538G-expressing clones, longitudinal analysis for this mutation in circulating free DNA may prove beneficial for informing more optimal therapeutic regimens.

Original languageEnglish (US)
Pages (from-to)176-189
Number of pages14
JournalOncology (Switzerland)
Issue number3
StatePublished - Feb 1 2018


  • Estrogen dependence
  • Estrogen receptor
  • Ligand-binding domain mutations
  • Metastatic breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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