Journal
CELL REPORTS
Volume 29, Issue 11, Pages 3405-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.008
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Funding
- Breast International Group (BIG)
- Spanish Breast Cancer Cooperative Group SOLTI
- BrEAST Data Center
- National Institutes of Health (NIH) [R01 CA58961]
- NCI career development award [R00 CA140948]
- NIH [R03 CA208384]
- Mary Kay Foundation
- NIH Centers of Biomedical Research Excellence (COBRE) grant [GM103534]
- Cancer Center core grant [P30 CA23108]
- Hitchcock Foundation
- Rosalin Borison Memorial pre-doctoral fellowship
- Dartmouth Clinical and Translational Science Institute under National Center for Advancing Translational Sciences (NCATS) of the NIH [KL2TR001088]
- Fonds de la Recherche Scientifique (FNRS)
- Breast Cancer Research Foundation (BCRF)
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Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTVneu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.
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