期刊
MOLECULAR CANCER RESEARCH
卷 17, 期 12, 页码 2492-2507出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0264
关键词
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资金
- FRQS Reseau Recherche cancer axe sein and Quebec Breast Cancer Foundation
- Genome Quebec
- Canadian Research Society [21439]
- Canadian Institutes of Health Research [377429]
- McPeak Sirois Consortium
- JGH Foundation
- McGill University
- Bourse de recherche en cancer du sein (Profil moleculaire de la double resistance du cancer du sein triple negatif aux agents anti-tumoraux) [FIW-127602]
- Eileen Iwanicki Foundation
- Canadian Institutes of Health Research
- Breast Cancer Society of Canada (North Sarnia, Ontario, Canada)
- McGill Integrated Cancer Research Training Program
- Biotalent Canada
- Lady Davis Institute TD Studentship award
- Genome Canada GTP platform
- Segal McGill Chair in Molecular Oncology at McGill University (Montreal, Quebec, Canada)
- Warren Y. Soper Charitable Trust
- Alvin Segal Family Foundation
The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer.
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