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Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via β-hydroxybutyrate

Chun-Kai Huang,Po-Hao Chang,W. Kuo,Chi-Long Chen,Y. Jeng,King-Jen Chang,J. Shew,Chun-Mei Hu,Wen-Hwa Lee

Published 2017 in Nature Communications

ABSTRACT

Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. Here we find, through systematic screening, that primary mammary gland-derived adipocytes (MGDAs) promote growth of breast cancer cells that express monocarboxylate transporter 2 (MCT2) both in vitro and in vivo. We show that β-hydroxybutyrate is secreted by MGDAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, β-hydroxybutyrate is sufficient to promote tumorigenesis of a mouse xenograft model of MCT2-expressing breast cancer cells. Mechanistically we observe that upon co-culturing with MGDAs or treatment with β-hydroxybutyrate, breast cancer cells expressing MCT2 increase the global histone H3K9 acetylation and upregulate several tumour-promoting genes. These results suggest that adipocytes promote malignancy of MCT2-expressing breast cancer via β-hydroxybutyrate potentially by inducing the epigenetic upregulation of tumour-promoting genes. Invasion of the adipose tissue correlates with poor prognosis in breast cancer. Here, the authors show that mammary gland adipocytes promote malignancy via β-hydroxybutyrate, which acts on cancer cells through the monocarboxylate transporter MCT2 resulting in tumour-promoting epigenetic modifications.

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