A Novel Molecular Mechanism Regulating ER\(\alpha\) Activation/Repression and Degradation by BRCA1/1a/1b in Breast Cancer Cells

Abstract

BRCA1 mutation is linked to aggressive breast cancers. We have discovered a consensus SUMO modification site in the amino-terminal region of the BRCA1/1a/1b proteins. The mutation in this possible SUMO acceptor site (K 10 9 R) reduced the proteins' capacity to bind and suppress ligand-dependent ER\(\alpha\) transcriptional activity in breast cancer cells. In addition, we discovered that Ubc9, a SUMO E2-conjugating enzyme, binds BRCA1 proteins. We identified the minimal BRCA1 domain (1-182 aa) required for both in vitro binding to Ubc9 and controlling ER\(\alpha\) activity. BRCA1 Mutant #1 (K109 R) and cancer-predisposing Mutant #4 (C61G) were impaired in their ability to both bind, as well as modulate Ubc9 mediated SUMO-dependent/independent E2-induced ER\(\alpha\) transcriptional activity in breast cancer cells. This is the first study to show Ubc9 is involved in the BRCA1 E3 ubiquitin ligase-mediated degradation of ER\(\alpha\). These findings point to a novel role for BRCA1 in controlling the dynamic cycles of SUMO and ubiquitin modifications necessary for ER\(\alpha\) turnover. Deregulation of this molecular switch as a result of BRCA1 failure leads to breast cancers that are either ER-negative or positive.

This study will help in designing novel BRCA1 function-based personalized targeted treatment for these aggressive breast cancers.