An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer

Mohammad Sultan; Jacob T. Nearing; Justin M. Brown; Thomas T. Huynh; Brianne M. Cruickshank; Emily Lamoureaux; Dejan Vidovic; Margaret L. Dahn; Wasundara Fernando; Krysta M. Coyle; Carman A. Giacomantonio; Morgan G.I. Langille; Paola Marcato

doi:10.1002/1878-0261.12964

An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer

Mohammad Sultan, Jacob T. Nearing, Justin M. Brown, Thomas T. Huynh, Brianne M. Cruickshank, Emily Lamoureaux, Dejan Vidovic, Margaret L. Dahn, Wasundara Fernando, Krysta M. Coyle, Carman A. Giacomantonio, Morgan G.I. Langille, Paola Marcato

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8 Citations (Scopus)

Abstract

Paclitaxel is a common breast cancer drug; however, some tumors are resistant. The identification of biomarkers for paclitaxel resistance or sensitivity would enable the development of strategies to improve treatment efficacy. A genome-wide in vivo shRNA screen was performed on paclitaxel-treated mice with MDA-MB-231 tumors to identify genes associated with paclitaxel sensitivity or resistance. Gene expression of the top screen hits was associated with tumor response (resistance or sensitivity) among patients who received neoadjuvant chemotherapy containing paclitaxel. We focused our validation on screen hit B-cell lymphoma 6 (BCL6), which is a therapeutic target in cancer but for which no effects on drug response have been reported. Knockdown of BCL6 resulted in increased tumor regression in mice treated with paclitaxel. Similarly, inhibiting BCL6 using a small molecule inhibitor enhanced paclitaxel treatment efficacy both in vitro and in vivo in breast cancer models. Mechanism studies revealed that reduced BCL6 enhances the efficacy of paclitaxel by inducing sustained G1/S arrest, concurrent with increased apoptosis and expression of target gene cyclin-dependent kinase inhibitor 1A. In summary, the genome-wide shRNA knockdown screen has identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer.

Original language	English
Pages (from-to)	2046-2064
Number of pages	19
Journal	Molecular Oncology
Volume	15
Issue number	8
DOIs	https://doi.org/10.1002/1878-0261.12964
Publication status	Published - Aug 2021

Bibliographical note

Funding Information:
Support was provided by grant funding to PM, MGIL, and CAG by the Cancer Research Society (operating grant number 25057) and the Nova Scotia Health Research Foundation (NSHRF, Establishment grant), and a Discovery grant from NSERC to MGIL. MS, JTN, DV, BMC, TTH, and MLD were supported by a Nova Scotia Research and Innovation Graduate scholarship. MS, DV, BMC, MLD, and KMC were also supported Killam Laureate scholarship. MLD and KMC were also supported by a CGS‐D award from the CIHR, and MS, JTN, JMB, MLD, and KMC were also supported by Scotia Scholar studentships from Research Nova Scotia (formerly the Nova Scotia Health Research Foundation). JMB and TTH were also supported by Cancer Research Training Program (CRTP) studentships from the Beatrice Hunter Cancer Research Institute (BHCRI), the Terry Fox Research Institute, and the Canadian Imperial Bank of Commerce.

Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

ASJC Scopus Subject Areas

Molecular Medicine
Genetics
Oncology
Cancer Research

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

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

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10.1002/1878-0261.12964

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Sultan, M., Nearing, J. T., Brown, J. M., Huynh, T. T., Cruickshank, B. M., Lamoureaux, E., Vidovic, D., Dahn, M. L., Fernando, W., Coyle, K. M., Giacomantonio, C. A., Langille, M. G. I., & Marcato, P. (2021). An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer. Molecular Oncology, 15(8), 2046-2064. https://doi.org/10.1002/1878-0261.12964

Sultan, M, Nearing, JT, Brown, JM, Huynh, TT, Cruickshank, BM, Lamoureaux, E, Vidovic, D, Dahn, ML, Fernando, W, Coyle, KM, Giacomantonio, CA , Langille, MGI & Marcato, P 2021, 'An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer', Molecular Oncology, vol. 15, no. 8, pp. 2046-2064. https://doi.org/10.1002/1878-0261.12964

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title = "An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer",

abstract = "Paclitaxel is a common breast cancer drug; however, some tumors are resistant. The identification of biomarkers for paclitaxel resistance or sensitivity would enable the development of strategies to improve treatment efficacy. A genome-wide in vivo shRNA screen was performed on paclitaxel-treated mice with MDA-MB-231 tumors to identify genes associated with paclitaxel sensitivity or resistance. Gene expression of the top screen hits was associated with tumor response (resistance or sensitivity) among patients who received neoadjuvant chemotherapy containing paclitaxel. We focused our validation on screen hit B-cell lymphoma 6 (BCL6), which is a therapeutic target in cancer but for which no effects on drug response have been reported. Knockdown of BCL6 resulted in increased tumor regression in mice treated with paclitaxel. Similarly, inhibiting BCL6 using a small molecule inhibitor enhanced paclitaxel treatment efficacy both in vitro and in vivo in breast cancer models. Mechanism studies revealed that reduced BCL6 enhances the efficacy of paclitaxel by inducing sustained G1/S arrest, concurrent with increased apoptosis and expression of target gene cyclin-dependent kinase inhibitor 1A. In summary, the genome-wide shRNA knockdown screen has identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer.",

author = "Mohammad Sultan and Nearing, {Jacob T.} and Brown, {Justin M.} and Huynh, {Thomas T.} and Cruickshank, {Brianne M.} and Emily Lamoureaux and Dejan Vidovic and Dahn, {Margaret L.} and Wasundara Fernando and Coyle, {Krysta M.} and Giacomantonio, {Carman A.} and Langille, {Morgan G.I.} and Paola Marcato",

note = "Funding Information: Support was provided by grant funding to PM, MGIL, and CAG by the Cancer Research Society (operating grant number 25057) and the Nova Scotia Health Research Foundation (NSHRF, Establishment grant), and a Discovery grant from NSERC to MGIL. MS, JTN, DV, BMC, TTH, and MLD were supported by a Nova Scotia Research and Innovation Graduate scholarship. MS, DV, BMC, MLD, and KMC were also supported Killam Laureate scholarship. MLD and KMC were also supported by a CGS‐D award from the CIHR, and MS, JTN, JMB, MLD, and KMC were also supported by Scotia Scholar studentships from Research Nova Scotia (formerly the Nova Scotia Health Research Foundation). JMB and TTH were also supported by Cancer Research Training Program (CRTP) studentships from the Beatrice Hunter Cancer Research Institute (BHCRI), the Terry Fox Research Institute, and the Canadian Imperial Bank of Commerce. Publisher Copyright: {\textcopyright} 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

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AU - Huynh, Thomas T.

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AU - Lamoureaux, Emily

AU - Vidovic, Dejan

AU - Dahn, Margaret L.

AU - Fernando, Wasundara

AU - Coyle, Krysta M.

AU - Giacomantonio, Carman A.

AU - Langille, Morgan G.I.

AU - Marcato, Paola

N1 - Funding Information: Support was provided by grant funding to PM, MGIL, and CAG by the Cancer Research Society (operating grant number 25057) and the Nova Scotia Health Research Foundation (NSHRF, Establishment grant), and a Discovery grant from NSERC to MGIL. MS, JTN, DV, BMC, TTH, and MLD were supported by a Nova Scotia Research and Innovation Graduate scholarship. MS, DV, BMC, MLD, and KMC were also supported Killam Laureate scholarship. MLD and KMC were also supported by a CGS‐D award from the CIHR, and MS, JTN, JMB, MLD, and KMC were also supported by Scotia Scholar studentships from Research Nova Scotia (formerly the Nova Scotia Health Research Foundation). JMB and TTH were also supported by Cancer Research Training Program (CRTP) studentships from the Beatrice Hunter Cancer Research Institute (BHCRI), the Terry Fox Research Institute, and the Canadian Imperial Bank of Commerce. Publisher Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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N2 - Paclitaxel is a common breast cancer drug; however, some tumors are resistant. The identification of biomarkers for paclitaxel resistance or sensitivity would enable the development of strategies to improve treatment efficacy. A genome-wide in vivo shRNA screen was performed on paclitaxel-treated mice with MDA-MB-231 tumors to identify genes associated with paclitaxel sensitivity or resistance. Gene expression of the top screen hits was associated with tumor response (resistance or sensitivity) among patients who received neoadjuvant chemotherapy containing paclitaxel. We focused our validation on screen hit B-cell lymphoma 6 (BCL6), which is a therapeutic target in cancer but for which no effects on drug response have been reported. Knockdown of BCL6 resulted in increased tumor regression in mice treated with paclitaxel. Similarly, inhibiting BCL6 using a small molecule inhibitor enhanced paclitaxel treatment efficacy both in vitro and in vivo in breast cancer models. Mechanism studies revealed that reduced BCL6 enhances the efficacy of paclitaxel by inducing sustained G1/S arrest, concurrent with increased apoptosis and expression of target gene cyclin-dependent kinase inhibitor 1A. In summary, the genome-wide shRNA knockdown screen has identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer.

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An in vivo genome-wide shRNA screen identifies BCL6 as a targetable biomarker of paclitaxel resistance in breast cancer

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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