title: Molecular mechanism of SLC5A8 inactivation in breast cancer.
abstract: SLC5A8 is a putative tumor suppressor that is inactivated in more than 10 different types of cancer, but neither the oncogenic signaling responsible for SLC5A8 inactivation nor the functional relevance of SLC5A8 loss to tumor growth has been elucidated. Here, we identify oncogenic HRAS (HRAS(G12V)) as a potent mediator of SLC5A8 silencing in human nontransformed normal mammary epithelial cell lines and in mouse mammary tumors through DNMT1. Further, we demonstrate that loss of Slc5a8 increases cancer-initiating stem cell formation and promotes mammary tumorigenesis and lung metastasis in an HRAS-driven murine model of mammary tumors. Mammary-gland-specific overexpression of Slc5a8 (mouse mammary tumor virus-Slc5a8 transgenic mice), as well as induction of endogenous Slc5a8 in mice with inhibitors of DNA methylation, protects against HRAS-driven mammary tumors. Collectively, our results provide the tumor-suppressive role of SLC5A8 and identify the oncogenic HRAS as a mediator of tumor-associated silencing of this tumor suppressor in mammary glands. These findings suggest that pharmacological approaches to reactivate SLC5A8 expression in tumor cells have potential as a novel therapeutic strategy for breast cancer treatment.
authors.affiliation: Departments of Biochemistry and Molecular Biology.
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: Sonne R
authors.initials: SR
authors.lastname: Srinivas
authors.forename: Ellappan
authors.initials: E
authors.lastname: Babu
authors.forename: Lesleyann
authors.initials: L
authors.lastname: Hawthorn
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Schoenlein
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
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* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D027501:Monocarboxylic Acid Transporters; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; C476760:SLC5A8 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
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