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A functional genomic screen identifies the deubiquitinase USP11 as a novel transcriptional regulator of ERa in breast cancer

journal contribution
posted on 04.08.2021, 15:29 by Lisa Dwane, Aisling E O'Connor, Sudipto DasSudipto Das, Bruce Moran, Laoighse Mulrane, Adan Pinto-Fernandez, Elspeth WardElspeth Ward, Anna BlümelAnna Blümel, Brenton CavanaghBrenton Cavanagh, Brian Mooney, Annette M Dirac, Karin Jirström, Benedikt M Kessler, Triona Ni ChonghaileTriona Ni Chonghaile, Rene Bernards, William M Gallagher, Darran O'ConnorDarran O'Connor
Approximately 70% of breast cancers express estrogen receptor α (ERα) 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 ERα function may further our understanding of breast carcinogenesis and reveal new therapeutic opportunities. Here, we investigated the role of deubiquitinases (DUB) in regulating ERaα in breast cancer. An RNAi loss-offunction screen in breast cancer cells targeting all DUBs identified USP11 as a regulator of ERα transcriptional activity, which was further validated by assessment of direct transcriptional targets of ERα. USP11 expression was induced by estradiol, an effect that was blocked by tamoxifen and not observed in ERα-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 ERα 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 ERα-positive (ERα+) patients. Overall, this study highlights a novel role for USP11 in the regulation of ERα activity, where USP11 may represent a prognostic marker in ERa+ breast cancer. Significance: A newly identified role for USP11 in ERα transcriptional activity represents a novel mechanism of ERα regulation and a pathway to be exploited for the management of ER-positive breast cancer.

Funding

From population to patient: Leveraging systems medicine to personalise breast cancer treatment | Funder: Irish Cancer Society | Grant ID: CCRC13GAL

European Union Seventh Framework Programme under the RATHER project 258967

Science Foundation Ireland Career Development Award (15/CDA/3438)

Investigator Programme award OPTi-PREDICT (15/IA/3104)

SFI Strategic Partnership “Precision Oncology Ireland” (18/SPP/3522)

Dutch Cancer Society through the Oncode Institute

Irish Research Council

Human Frontiers Science Programme

UICC

European Association for Cancer Research

History

Comments

The original article is available at https://cancerres.aacrjournals.org

Published Citation

Dwane L et al. A functional genomic screen identifies the deubiquitinase USP11 as a novel transcriptional regulator of ERa in breast cancer. Cancer Res. 2020;80(22):5076-5088.

Publication Date

15 November 2020

PubMed ID

33004351

Department/Unit

  • Physiology and Medical Physics
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Cancer
  • Immunity, Infection and Inflammation

Publisher

American Association for Cancer Research (AACR)

Version

  • Accepted Version (Postprint)