A Functional Genomic Screen Identifies the Deubiquitinase USP11 as a Novel Transcriptional Regulator of ERα in Breast Cancer

Approximately 70% of breast cancers express estrogen receptor a (ER alpha) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted antiendocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating the mechanisms that control ER alpha function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here, we investigated the role of deubiquitinases (DUB) in regulating ER alpha in breast cancer. An RNAi loss-of-function screen in breast cancer cells targeting all DUBs identified USP11 as a regulator of ER alpha transcriptional activity, which was further validated by assessment of direct transcriptional targets of ER alpha. USP11 expression was induced by estradiol, an effect that was blocked by tamoxifen and not observed in ER alpha-negative cells. Mass spectrometry revealed a significant change to the proteome and ubiquitinome in USP11-knockdown (KD) cells in the presence of estradiol. RNA sequencing in LCC1 USP11-KD cells revealed significant suppression of cell-cycle-associated and ER alpha target genes, phenotypes that were not observed in LCC9 USP11-KD, antiendocrine-resistant cells. In a breast cancer patient cohort coupled with in silico analysis of publicly available cohorts, high expression of USP11 was significantly associated with poor survival in ER alpha-positive (ER alpha(+)) patients. Overall, this study highlights a novel role for USP11 in the regulation of ER alpha activity, where USP11 may represent a prognostic marker in ER alpha(+) breast cancer. Significance: A newly identified role for USP11 in ER alpha transcriptional activity represents a novel mechanism of ER alpha regulation and a pathway to be exploited for the management of ER-positive breast cancer.