A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells

Fabio Petrocca*, Gabriel Altschuler, ShenMynn Tan, MarcL Mendillo, Haoheng Yan, D. Joseph Jerry, AndrewL Kung, Winston Hide, TanA Ince, Judy Lieberman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen's 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal, and mesenchymal TNBC lines. Proteasome inhibition reduced growth of established basal-like TNBC tumors in mice and blocked tumor-initiating cell function and macrometastasis. Proteasome addiction in basal-like TNBCs was mediated by NOXA and linked to MCL-1 dependence.

Original languageEnglish (US)
Pages (from-to)182-196
Number of pages15
JournalCancer cell
Volume24
Issue number2
DOIs
StatePublished - Aug 12 2013

Funding

This work was supported by the Department of Defense Breast Cancer Research Program (to J.L., F.P., and S.M.T.), the National Cancer Institute (R01-CA146445 to T.A.I.), and the Breast Cancer Research Foundation (to T.A.I.). We thank Robert Weinberg for useful discussions, Caroline Shamu, Sean Johnston, and Stewart Rudnicki of ICCB-Longwood for invaluable help performing the screen, Giorgia Zadra for critical advice on histopathology, Natasha Barteneva and Ken Ketman for flow cytometry assistance, and members of the Lieberman laboratory for helpful suggestions. T.A.I. receives royalty payments for WIT medium and was a consultant to Stemgent, Inc. from 2008–2010.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Cell Biology

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