Abstract
Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.
Highlights
The tumour microenvironment is key to tumour growth
To explore the context-dependent role of CD36 in adipocytebreast cancer cell interaction, CD36 expression was examined in a direct co-culture of breast cancer cells (MCF10A, MCF-7, BT-483, HCC2218 and MDA-MB-468) and differentiated human adipocytes after 48 hours via qRT-PCR
The CD36+/CD44+ cell population in the co-cultured knockout-CD36 cells significantly decreased (Fig. 2G, H). These results indicate that the emergence of stem-cell-like traits in breast cancer cells is influenced in part by the adipocytes, and upregulated CD36 expression enhances the emergence of the CD36+/CD44+ cell population
Summary
The tumour microenvironment is key to tumour growth. Adipocyte-secreted interleukin-6 (IL-6) and leptin reportedly induce and regulate epithelial–mesenchymal transition (EMT) in cancer cells[3,4,5]. Adipocyte-secreted leptin activates targets that enhance stem cell renewal and chemoresistance[6,7]. Adipocytes release metabolites and biomolecules, which remodel tumour cell metabolism to enhance tumour growth. Adipocytes proximity to breast cancer cells allows breast cancer cells to parasite on their energy substrates and obtain metabolites, including lactate, glutamine and fatty acids, which are limited in the growing tumour environment[9,10,11]. There are emerging studies into the mechanisms of free fatty acid (FFA) import and metabolism in breast cancer microenvironment, several aspects of the process remain unexplored
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