This month’s featured article is from the lab of Wen-Hwa Lee at China Medical University in Taiwan and colleagues at National Taiwan University. The article about breast cancer research was published 10 Mar 2017 in the journal Nature Communications. This study focused on adipocytes in the mammary glands and their role in breast cancer tumor progression. Adipocytes have received little attention in breast cancer studies despite being abundant in breast tissue. Much more attention has been paid to breast cancer cells and their associated fibroblasts and macrophages. All of these cell types act to control the tumor microenvironment and contribute to cancer progression and metastasis.
The authors studied adipocytes both in vivo and in vitro. They created a co-culture of breast cancer cells and mammary gland-derived adipocytes (MGDAs) to assess whether MGDAs promote tumor progression, and to identify receptors that mediate communication between breast cancer cells and MGDAs. They found that MGDAs indeed promote different types of breast cancer, and that this effect was mediated by monocarboxylate transporter 2 (MCT2). They identified MCT2 via analysis of previously published microarray results.
Next, the authors sought to identify the soluble factors secreted by MCT2 in MGDAs that contributed to breast cancer progression. They reasoned that the soluble factor must be lactate, pyruvate, or beta-hydroxybutyrate – three known substrates of MCT2. Through a series of experiments, beta-hydroxybutyrate was isolated as the MCT2 substrate contributing to tumor progression. Notably, injection of beta-hydroxybutyrate in mouse xenograft models promoted tumor growth, but not in tumor models that were MCT2-depleted.
Lastly, the authors identified genes differentially expressed in breast cancer cells in a beta-hydroxybutyrate-dependent manner. To this end, they used Phalanx Biotech’s Human OneArray Whole Genome Microarray. The microarray results helped them identify IL-1beta and LCN2, and they further showed that the up-regulation of those genes was due to epigenetic changes, namely histone acetylation. Furthermore, IL-1beta and LCN2 appear to be potent biomarkers of breast cancer, as their elevated expression is correlated with poor prognosis.
In summary, the authors revealed a comprehensive model of the tumor microenvironment whereby beta-hydroxybutyrate is secreted by MGDAs and taken up by MCT2-expressing breast cancer cells. Once in the breast cancer cells, beta-hydroxybutyrate acts as an inhibitor of histone deacetylation, thereby inducing the expression of tumor-promoting genes. This pathway represents an exciting new avenue for further research and therapeutic potential.
Huang C-K et al. Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via b-hydroxybutyrate (2017). Nature Communications 8:17406.