Schematic illustrating the G protein-independent role of RGS6 in doxorubicin-induced apoptosis and antiproliferative signaling in the breast. a RGS6 is induced by doxorubicin (Dox) treatment and functions as a critical upstream mediator of reactive oxygen species (ROS)-dependent activation of the ataxia telangiectasia-mutated (ATM)-p53-apoptotic pathway in both mouse embryonic fibroblasts and breast cancer cells. Whether the RGS6-dependent upregulation of p53 in response to Dox induces autophagy by DNA-damage regulated autophagy modulator 1 (DRAM1) is unknown. b RGS6 is also a multifunctional tumor suppressor that simultaneously inhibits cell cycle progression and pro-growth signal downstream of human epidermal growth factor receptor 2 (HER2) and the estrogen receptor (ER). In addition, RGS6 functions as a scaffold protein to promote Tip60-mediated DNA (cytosine-5)-methyltransferase 1 (DNMT1) acetylation leading to its degradation and preventing DNMT1 silencing of pro-apoptotic genes. This represents an essential role of RGS6 in preventing reticular activating system (Ras)-induced oncogenesis. R7BP R7 family-binding protein, DMAP1 DNA methyltransferase1 associated protein 1, Met methylation, Ub ubiquitin, Ac acetylation, ERE estrogen response element. Image adapted from references (, , )