title: The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival.
abstract: GPR109A, a G-protein-coupled receptor, is activated by niacin and butyrate. Upon activation in colonocytes, GPR109A potentiates anti-inflammatory pathways, induces apoptosis, and protects against inflammation-induced colon cancer. In contrast, GPR109A activation in keratinocytes induces flushing by activation of Cox-2-dependent inflammatory signaling, and the receptor expression is upregulated in human epidermoid carcinoma. Thus, depending on the cellular context and tissue, GPR109A functions either as a tumor suppressor or a tumor promoter. However, the expression status and the functional implications of this receptor in the mammary epithelium are not known. Here, we show that GPR109A is expressed in normal mammary tissue and, irrespective of the hormone receptor status, its expression is silenced in human primary breast tumor tissues, breast cancer cell lines, and in tumor tissues of three different murine mammary tumor models. Functional expression of this receptor in human breast cancer cell lines decreases cyclic AMP production, induces apoptosis, and blocks colony formation and mammary tumor growth. Transcriptome analysis revealed that GPR109A activation inhibits genes, which are involved in cell survival and antiapoptotic signaling, in human breast cancer cells. In addition, deletion of Gpr109a in mice increased tumor incidence and triggered early onset of mammary tumorigenesis with increased lung metastasis in MMTV-Neu mouse model of spontaneous breast cancer. These findings suggest that GPR109A is a tumor suppressor in mammary gland and that pharmacologic induction of this gene in tumor tissues followed by its activation with agonists could be an effective therapeutic strategy to treat breast cancer.
authors.affiliation: Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Biostatistics and Epidemiology, and Pathology; Cancer Center; Vision Science Discovery Institute, Georgia Regents University; Augusta, Georgia.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Pathania
authors.forename: Sabarish
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.forename: Ravi N
authors.initials: RN
authors.lastname: Padia
authors.forename: Ling
authors.initials: L
authors.lastname: Lan
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.forename: Lesleyann
authors.initials: L
authors.lastname: Hawthorn
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002087:Butyrates / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009525:Niacin / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*
chemical_list: D002087:Butyrates; C530636:HCAR2 protein, human; C473652:Hcar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin