Abstract
Luminal breast cancers account for 70%-80% of total breast cancer cases. More than half of luminal breast cancers either relapse after treatment or lose their luminal features, resulting in poorly differentiated cancers with enhanced invasiveness and metastasis, yet the mechanisms remain largely elusive. In this study, we demonstrated that Ubiquitin-specific protease 11 (USP11) suppresses the proliferation and migration of luminal epithelial and tumor cells in vitro, but not basal-like tumor cells. Consistently, USP11 inhibits luminal tumorigenesis and metastasis, but promotes basal-like tumorigenesis in vivo. Mechanistically, USP11 positively regulates GATA3, p27, and ERα in a deubiquitinase activity-dependent manner. USP11 deubiquitinates GATA3, which subsequently binds to and transcriptionally activates CDKN1B (encoding p27). USP11 stimulates CDKN1B and ESR1 (encoding ERα) transcription in a GATA3-dependent manner. GATA3 knockdown reverses the increase in p27 and ERα and the decrease in cell proliferation and migration induced by USP11 overexpression, and p27 knockdown rescues the proliferative inhibition induced by USP11 or GATA3 overexpression in luminal tumorigenesis. USP11 overexpression sensitizes luminal breast cancer cells to tamoxifen treatment. The expression levels of USP11, GATA3, p27, and ERα are positively correlated with each other in human breast tumors and cell lines. We thus identify a novel USP11-GATA3 axis that governs luminal cell fate and restrains luminal cell proliferation and migration during mammary tumor development and metastasis.