Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression.

Maity B, Stewart A, O'Malley Y, Askeland RW, Sugg SL, Fisher RA
Carcinogenesis. 2013 34 (8): 1747-55

PMID: 23598467 · PMCID: PMC3731806 · DOI:10.1093/carcin/bgt128

Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6(-/-) mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6(-/-) mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6(-/-) animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6(-/-) mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6(-/-) mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6(-/-) but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors.

MeSH Terms (22)

9,10-Dimethyl-1,2-benzanthracene Animals Apoptosis Ataxia Telangiectasia Mutated Proteins Breast Neoplasms Carcinogenesis Cell Line, Tumor Disease Progression DNA Damage Epithelial Cells ErbB Receptors Female Humans Mammary Neoplasms, Experimental MCF-7 Cells Mice Mice, Inbred C57BL Reactive Oxygen Species Receptors, Estrogen RGS Proteins Signal Transduction Tumor Suppressor Protein p53

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