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

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.

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

“…Similar findings with metabolic coupling between stromal and cancer cells involving lactate, pyruvate, beta-hydroxybutyrate, acetate, fatty acids, glutamine and alanine have been discovered in many human malignancies including breast, ovarian, prostate, liver, colon, pancreatic and head and neck squamous cell cancer (HNSCC) [23] [29] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]. …”

Co-culture With Human Breast Adipocytes Differentially Regulates Protein Abundance in Breast Cancer Cells

“…Thus, studies investigating proteomic and phenotypic changes in breast cancer cells are clinically important. Previously, the differential regulation of rationally targeted proteins has been investigated following co-culture with CAA (14,17,18). In this study, we identified global protein abundance and associated pathways that are differentially regulated in two well-characterised breast cancer cell lines, representing key breast cancer molecular subtypes (hormone receptor positive, MCF7; triple negative, MDA-MB-231), following 3-day transwell co-culture with human breast adipocytes.…”

“…In vitro studies, using transwell (non-contact) co-culture of mature adipocytes with breast cancer cells, have established that CAA promote breast cancer cell proliferation, viability, migration and invasion (2, 8, [13][14][15][16][17][18]. Recent evidence suggests that cross talk with CAA induces breast cancer cell invasiveness, in part, through metabolic remodelling of the cancer cell, promoting a shift towards increased mitochondrial fatty acid oxidation (17,19).…”

Adipocytes in Breast Cancer, the Thick and the Thin

“…Importantly, the coexistence of adipocytes and tumor cells potentiates both ketogenesis in adipocytes as well as ketolytic activity in BC cells [142]. Additionally, it was shown that β-hydroxybutyrate secreted from adipocytes enhanced BC cells malignancy in vitro, upregulating several tumor-promoting genes in BC cells [144]. Induction of ketone-specific gene signature was shown to be associated with worse outcomes in BC patients [145].…”