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

14 Citations (Scopus)

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 - Nov 6 2013

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Breast Neoplasms
Neoplasms
Human Mammary Glands
Breast
Mouse mammary tumor virus
Neoplastic Stem Cells
DNA Methylation
Transgenic Mice
Carcinogenesis
Epithelial Cells
Pharmacology
Neoplasm Metastasis
Cell Line
Lung
Growth
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Elangovan, S., Pathania, R., Ramachandran, S., Ananth, S., Padia, R. N., Srinivas, S. R., ... 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

Molecular mechanism of SLC5A8 inactivation in breast cancer. / Elangovan, Selvakumar; Pathania, Rajneesh; Ramachandran, Sabarish; Ananth, Sudha; Padia, Ravi N.; Srinivas, Sonne R.; Babu, Ellappan; Hawthorn, Lesleyann; Schoenlein, Patricia V; Boettger, Thomas; Smith, Sylvia B; Prasad, Puttur D; Ganapathy, Vadivel; Thangaraju, Muthusamy.

In: Molecular and Cellular Biology, Vol. 33, No. 19, 06.11.2013, p. 3920-3935.

Research output: Contribution to journalArticle

Elangovan, S, Pathania, R, Ramachandran, S, Ananth, S, Padia, RN, Srinivas, SR, Babu, E, Hawthorn, L, Schoenlein, PV, Boettger, T, Smith, SB, Prasad, PD, Ganapathy, V & Thangaraju, M 2013, 'Molecular mechanism of SLC5A8 inactivation in breast cancer', Molecular and Cellular Biology, vol. 33, no. 19, pp. 3920-3935. https://doi.org/10.1128/MCB.01702-12
Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Srinivas SR et al. Molecular mechanism of SLC5A8 inactivation in breast cancer. Molecular and Cellular Biology. 2013 Nov 6;33(19):3920-3935. https://doi.org/10.1128/MCB.01702-12
Elangovan, Selvakumar ; Pathania, Rajneesh ; Ramachandran, Sabarish ; Ananth, Sudha ; Padia, Ravi N. ; Srinivas, Sonne R. ; Babu, Ellappan ; Hawthorn, Lesleyann ; Schoenlein, Patricia V ; Boettger, Thomas ; Smith, Sylvia B ; Prasad, Puttur D ; Ganapathy, Vadivel ; Thangaraju, Muthusamy. / Molecular mechanism of SLC5A8 inactivation in breast cancer. In: Molecular and Cellular Biology. 2013 ; Vol. 33, No. 19. pp. 3920-3935.
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