XAF1 destabilizes estrogen receptor alpha through the assembly of a BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis

Abstract

X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, its candidacy as a suppressor in the pathogenesis of breast cancer remains undefined. Here, we report that XAF1 acts as a molecular switch in estrogen (E2)-mediated cell-fate decisions favoring apoptosis over cell proliferation. XAF1 promoter hypermethylation is observed predominantly in estrogen receptor alpha (ER alpha)-positive versus ER alpha-negative tumor cells and associated with attenuated apoptotic response to E2. XAF1 is activated by E2 through a G protein-coupled estrogen receptor-mediated non-genomic pathway and induces ER alpha degradation and apoptosis while it is repressed by ER alpha for E2 stimulation of cell proliferation. The XAF1-ER alpha mutual antagonism dictates the outcomes of E2 signaling and its alteration is linked to the development of E2-resistant tumors. Mechanistically, XAF1 destabilizes ER alpha through the assembly of breast cancer-associated gene 1 (BRCA1)-mediated destruction complex. XAF1 interacts with ER alpha and BRCA1 via the zinc finger (ZF) domains 5/6 and 4, respectively, and the mutants lacking either of these domains fail to drive ER alpha ubiquitination and apoptosis. E2-induced regression of XAF1(+/+) tumors is abolished by XAF1 depletion while XAF1(-/-) tumors recover E2 response by XAF1 restoration. XAF1 and ER alpha expression show an inverse correlation in primary breast tumors, and XAF1 expression is associated with the overall survival of patients with ER alpha-positive but not ER alpha-negative cancer. Together, this study uncovers an important role for the XAF1-ER alpha antagonism as a linchpin to govern E2-mediated cell-fate decisions, illuminating the mechanistic consequence of XAF1 alteration in breast tumorigenesis.