Molecular mechanism of SLC5A8 inactivation in breast cancer

Selvakumar Elangovan, Rajneesh Pathania, Sabarish Ramachandran, Sudha Ananth, Ravi N. Padia, Sonne R. Srinivas, Ellappan Babu, Lesleyann Hawthorn, Patricia V. Schoenlein, Thomas Boettger, Sylvia B. Smith, Puttur D. Prasad, Vadivel Ganapathy, Muthusamy Thangaraju

Research output: Contribution to journalArticle

20 Scopus citations

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 (HRASG12V) 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 HRASdriven 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.

Original languageEnglish (US)
Pages (from-to)3920-3935
Number of pages16
JournalMolecular and Cellular Biology
Volume33
Issue number19
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Elangovan, S., Pathania, R., Ramachandran, S., Ananth, S., Padia, R. N., Srinivas, S. R., Babu, E., Hawthorn, L., Schoenlein, P. V., Boettger, T., Smith, S. B., Prasad, P. D., Ganapathy, V., & Thangaraju, M. (2013). Molecular mechanism of SLC5A8 inactivation in breast cancer. Molecular and Cellular Biology, 33(19), 3920-3935. https://doi.org/10.1128/MCB.01702-12