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

TitleA Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsPetrocca F, Altschuler G, Tan SM, Mendillo ML, Yan H, Jerry JD, Kung AL, Hide W, Ince TA, Lieberman J
JournalCancer Cell
Volume24
Issue2
Pagination182-96
Date Published2013 Aug 12
ISSN1878-3686
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.

DOI10.1016/j.ccr.2013.07.008
Alternate JournalCancer Cell
PubMed ID23948298