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

Carcinogenesis. 2013 Aug;34(8):1747-55. doi: 10.1093/carcin/bgt128. Epub 2013 Apr 18.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


  • RGS Proteins
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Rgs6 protein, mouse
  • Tumor Suppressor Protein p53
  • 9,10-Dimethyl-1,2-benzanthracene
  • EGFR protein, mouse
  • ErbB Receptors
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse