TY - JOUR
T1 - Molecular mechanism of SLC5A8 inactivation in breast cancer
AU - Elangovan, Selvakumar
AU - Pathania, Rajneesh
AU - Ramachandran, Sabarish
AU - Ananth, Sudha
AU - Padia, Ravi N.
AU - Srinivas, Sonne R.
AU - Babu, Ellappan
AU - Hawthorn, Lesleyann
AU - Schoenlein, Patricia V.
AU - Boettger, Thomas
AU - Smith, Sylvia B.
AU - Prasad, Puttur D.
AU - Ganapathy, Vadivel
AU - Thangaraju, Muthusamy
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1128/MCB.01702-12
DO - 10.1128/MCB.01702-12
M3 - Article
C2 - 23918800
AN - SCOPUS:84886790779
SN - 0270-7306
VL - 33
SP - 3920
EP - 3935
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 19
ER -