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

Chun-Kai Huang; Po-Hao Chang; Wen-Hung Kuo; Chi-Long Chen; Yung-Ming Jeng; King-Jen Chang; Jin-Yuh Shew; Chun-Mei Hu; Wen-Hwa Lee

doi:10.1038/ncomms14706

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

Nat Commun. 2017 Mar 10:8:14706. doi: 10.1038/ncomms14706.

Authors

Chun-Kai Huang^{1

2}, Po-Hao Chang², Wen-Hung Kuo³, Chi-Long Chen⁴, Yung-Ming Jeng⁵, King-Jen Chang^{3

6}, Jin-Yuh Shew^{1

2}, Chun-Mei Hu², Wen-Hwa Lee^{1

2

7}

Affiliations

¹ Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
² Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
³ Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
⁴ Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
⁵ Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan.
⁶ Cheng Chin General Hospital, Taichung 407, Taiwan.
⁷ Graduate Institute of New Drug Development, China Medical University, Taichung 404, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / metabolism*
3-Hydroxybutyric Acid / pharmacology
Acetylation
Adipocytes / metabolism*
Adipocytes / pathology
Adipose Tissue / metabolism
Adipose Tissue / pathology
Animals
Armadillo Domain Proteins / genetics
Armadillo Domain Proteins / metabolism
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Carcinogenesis / drug effects
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology
Cell Line, Tumor
Coculture Techniques
Epigenesis, Genetic*
Female
Glypicans / genetics
Glypicans / metabolism
Histones / genetics*
Histones / metabolism
Humans
MCF-7 Cells
Mammary Glands, Human / metabolism
Mammary Glands, Human / pathology
Mice
Mice, Inbred NOD
Monocarboxylic Acid Transporters / genetics*
Monocarboxylic Acid Transporters / metabolism
Neoplasm Transplantation
Oncogene Proteins / genetics
Oncogene Proteins / metabolism
Phosphoric Diester Hydrolases / genetics
Phosphoric Diester Hydrolases / metabolism
Primary Cell Culture
Pyrophosphatases / genetics
Pyrophosphatases / metabolism
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

ADGRG6 protein, human
ARMCX1 protein, human
Armadillo Domain Proteins
FRMD5 protein, human
GPC6 protein, human
Glypicans
Histones
Monocarboxylic Acid Transporters
Oncogene Proteins
Receptors, G-Protein-Coupled
SLC16A7 protein, human
Tumor Suppressor Proteins
Phosphoric Diester Hydrolases
ectonucleotide pyrophosphatase phosphodiesterase 1
Pyrophosphatases
3-Hydroxybutyric Acid