Role of the fatty acid transporter CD36 in the therapeutic resistance of HER2-positive breast cancer

Manabu Kurokawa, PhD
Kent State University

Fatty acids (FAs) play essential roles in cancer metabolism for signal transduction, energy production, and membrane biogenesis. In general, cancer cells acquire FAs from exogenous sources, mediated by the FA transporter CD36, and/or endogenously through de novo lipogenesis involving FA synthase (FASN). High levels of FASN expression are associated with poor prognosis in various cancers, including breast cancer. In turn, FASN inhibition can induce apoptosis in cancer cells. While the functional significance of FASN in cancer metabolism has been extensively studied, the role of CD36 in cancer progression remains poorly understood. 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 MMTV-neu 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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