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

Biswanath Maity; Adele Stewart; Yunxia O’Malley; Ryan W Askeland; Sonia L Sugg; Rory A Fisher

doi:10.1093/carcin/bgt128

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

Journal article

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

Biswanath Maity, Adele Stewart, Yunxia O’Malley, Ryan W Askeland, Sonia L Sugg and Rory A Fisher

Carcinogenesis (New York), Vol.34(8), pp.1747-1755

08/2013

DOI: 10.1093/carcin/bgt128

PMCID: PMC3731806

PMID: 23598467

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Abstract

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.

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Title: Subtitle: Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression
Creators: Biswanath Maity - ,
Adele Stewart - ,
Yunxia O’Malley - and
Ryan W Askeland - ,
Sonia L Sugg - and
Rory A Fisher - ,
Resource Type: Journal article
Publication Details: Carcinogenesis (New York), Vol.34(8), pp.1747-1755
Publisher: Oxford University Press; UK
DOI: 10.1093/carcin/bgt128
PMID: 23598467
PMCID: PMC3731806
ISSN: 0143-3334
eISSN: 1460-2180
Language: English
Date published: 08/2013
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Surgery; Gastroenterology, Hepatology, Pancreatology, and Nutrition; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040454502771

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