Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression
| Autor: | Rory A. Fisher, Ryan W. Askeland, Adele Stewart, Biswanath Maity, Sonia L. Sugg, Yunxia O'Malley |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_specialty Carcinogenesis DNA damage 9 10-Dimethyl-1 2-benzanthracene Estrogen receptor Original Manuscript Apoptosis Breast Neoplasms Ataxia Telangiectasia Mutated Proteins Tumor initiation Biology medicine.disease_cause Mice Breast cancer Cell Line Tumor Internal medicine medicine Animals Humans Cell growth Mammary Neoplasms Experimental Cancer Epithelial Cells General Medicine medicine.disease ErbB Receptors Mice Inbred C57BL Endocrinology Receptors Estrogen Disease Progression MCF-7 Cells Cancer research Female Tumor Suppressor Protein p53 Signal transduction Reactive Oxygen Species RGS Proteins DNA Damage Signal Transduction |
| Zdroj: | Carcinogenesis. 34:1747-1755 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgt128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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