title: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chun-Kai
authors.initials: CK
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Po-Hao
authors.initials: PH
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.|Cheng Chin General Hospital, Taichung 407, Taiwan.
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.|Graduate Institute of New Drug Development, China Medical University, Taichung 404, Taiwan.
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism* / Q000494:pharmacology; D000107:Acetylation; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D044127:Epigenesis, Genetic; D005260:Female; D053673:Glypicans / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C488660:ADGRG6 protein, human; C422103:ARMCX1 protein, human; D051186:Armadillo Domain Proteins; C000594766:FRMD5 protein, human; C120300:GPC6 protein, human; D053673:Glypicans; D006657:Histones; D027501:Monocarboxylic Acid Transporters; D015513:Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; C490427:SLC16A7 protein, human; D025521:Tumor Suppressor Proteins; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases; D020155:3-Hydroxybutyric Acid