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

doi:10.1016/j.ccr.2013.07.008

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

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	182-196
Number of pages	15
Journal	Cancer cell
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2013.07.008
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2013.07.008

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

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.",

author = "Fabio Petrocca and Gabriel Altschuler and ShenMynn Tan and MarcL Mendillo and Haoheng Yan and Jerry, {D. Joseph} and AndrewL Kung and Winston Hide and TanA Ince and Judy Lieberman",

note = "Funding Information: 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. ",

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N2 - 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.

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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