期刊
MOLECULAR ONCOLOGY
卷 15, 期 8, 页码 2046-2064出版社
WILEY
DOI: 10.1002/1878-0261.12964
关键词
breast cancer; paclitaxel; BCL6; shRNA screen; biomarkers
类别
资金
- Cancer Research Society [25057]
- Nova Scotia Health Research Foundation (NSHRF, Establishment grant)
- NSERC
- Nova Scotia Research and Innovation Graduate scholarship
- Killam Laureate scholarship
- CGS-D award from the CIHR
- Scotia Scholar studentships from Research Nova Scotia
- Cancer Research Training Program (CRTP) studentships from the Beatrice Hunter Cancer Research Institute (BHCRI)
- Terry Fox Research Institute
- Canadian Imperial Bank of Commerce
The study identified BCL6 as a potential targetable resistance biomarker of paclitaxel response in breast cancer, with knockdown of BCL6 resulting in increased tumor regression and enhanced paclitaxel treatment efficacy. This suggests that targeting BCL6 may be a promising strategy to improve the response to paclitaxel in breast cancer patients.
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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