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

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.

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

“…An RGS6 enhancer could also be beneficial as a novel cancer therapeutic. RGS6 has been proposed as a tumour suppressor in several types of cancer, including bladder, lung and breast cancer (Berman et al, 2004;Gu et al, 2006;Maity et al, 2011;Maity et al, 2013). While the effects of RGS6 in the CNS seem to mainly be mediated through is canonical GAP activity, its action as a tumour suppressor is mediated through non-G protein mechanisms (Maity et al, 2011).…”

Changing of RGS Transcripts Levels by Low-Dose-Rate Ionizing Radiation in Mouse Testis

“…Under cellular stress conditions, such as proteasome-mediated stress or mild heat stress, RGS6 is translocated into the nucleoli [24]. RGS6 also modulates doxorubicin-mediated ATM and p53 activation [25] and suppressed breast cancer initiation and progression [26]. Furthermore, the indirect interaction of RGS6 and DNA methyltransferase (Dnmt1), which is considered as a novel oncogene that suppresses the transcription of pro-apoptotic genes, have also been reported [27].…”

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

“…In particular, RGS6−/− mice chronically exposed to alcohol lacked alcohol-induced cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia. This reduction in alcohol-induced peripheral tissue damage is believed to involve RGS6's direct or indirect regulation of reactive oxygen species (ROS) production and the apoptotic cascade (21) similar to its functions in cancer suppression (27)(28)(29)(30).…”

“…These findings provided the first glimpse into the critical role of RGS6 as a tumor suppressor and mediator of DNA damage signaling, which would be further demonstrated through subsequent studies. Of particular interest, it was found that these activities were due to G protein-independent actions of RGS6 (28).…”

“…RGS6 specific modulation of Gα i/o protein activity has been implicated in the regulation of several disease states, particularly in the central nervous system (CNS), including the following: alcoholism (21), anxiety/depression (22), Parkinson's disease (23), and potentially Alzheimer's disease (24), schizophrenia (25), and vision (26). However, RGS6 is also unique in that it remains the only member of the R7 protein family that has been demonstrated to regulate G protein-independent pathways, as evidenced by its compelling pro-apoptotic and tumor suppressor actions in cancer (27)(28)(29)(30).…”