1 Institute for Research in Immunology and Cancer, Montréal, QC, H3C 3J7, Canada.
2 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada.
3 PERFORM Centre, Concordia University, Montréal, QC, H4B 1R6, Canada.
4 Institute for Research in Immunology and Cancer, Montréal, QC, H3C 3J7, Canada. sylvie.mader@umontreal.ca.
5 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada. sylvie.mader@umontreal.ca.

Role of SUMOylation in differential ERa transcriptional repression by tamoxifen and fulvestrant in breast cancer cells.

Oncogene. 2019 02;38(7):1019-1037

Authors: Traboulsi T, El Ezzy M, Dumeaux V, Audemard E, Mader S

Abstract

Antiestrogens (AEs) are widely used for treatment of estrogen receptor alpha (ERa)-positive breast cancer, but display variable degrees of partial agonism in estrogen target tissues and breast cancer (BC) cells. The fact that BC cells resistant to selective ER modulators (SERMs) like tamoxifen (Tam) can still be sensitive to pure AEs, also called selective ER downregulators, suggests different mechanisms of action, some of which may contribute to the more complete suppression of estrogen target genes by pure AEs. We report herein that pure AEs such as fulvestrant induce transient binding of ERa to DNA, followed by rapid release after 30-40?min without loss of nuclear localization. Loss of DNA binding preceded receptor degradation and was not prevented by proteasome inhibition. Chromatin was less accessible in the presence of fulvestrant than with estradiol or Tam as early as 20?min following treatment, suggesting that chromatin remodeling by pure AEs at ERa target regions prevents transcription in spite of receptor binding. SUMO2/3 marks were detected on chromatin at the peak of ERa binding in cells treated with pure AEs, but not SERMs. Furthermore, decreasing SUMOylation by overexpressing the deSUMOylase SENP1 significantly delayed receptor release from DNA and de-repressed expression of estrogen target genes in the presence of fulvestrant, both in ERa-expressing MCF-7 cells and in transiently transfected ER-negative SK-BR-3 cells. Finally, mutation V534E, identified in a breast metastasis resistant to hormonal therapies, prevented ERa modification and resulted in increased transcriptional activity of estrogen target genes in the presence of fulvestrant in SK-BR-3 cells. Together, our results establish a role for SUMOylation in achieving a more complete transcriptional shut-off of estrogen target genes by pure AEs vs. SERMs in BC cells.

PMID: 30190545 [PubMed - indexed for MEDLINE]