Abstract Background: Agents that introduce genotoxic stresses in mammalian cells, such as paclitaxel (Taxol) or ionizing radiation activate a complex array of cellular responses, including p53 activation. As a component of the response to acute stress, p53 has a well-established role in protecting against cancer development. It is not surprising that half of all human tumors have mutated p53. We asked how then tumors are initiated in the cells that carry wild-type p53 allele?Material and Methods: Here we report the identification of a potential novel mechanism that induces tumor formation in p53 wild-type cells. Overexpression of the proto-oncogene, BRCA1-IRIS in human mammary epithelial (HME) cells not only upregulates the expression of the serine/threonine phosphatase; Wild-type p53-Induced Phosphatase (WIP1) through induction of p53 expression but also increases the WIP1 gene copy number in these cells. WIP1 is a negative regulator of p53 as well as p38MAPK. Both proteins are involved in arresting and/or killing cells with extensive genotoxic stresses. Failure to arrest or die in response to massive genotoxic stress leads to the propagation of damaged cells and the development of cancer. BRCA1-IRIS overexpressing cells failed to arrest or die when exposed to UV radiation or Taxol. In fact, treatment of normal HME cells with UV or Taxol upregulated the expression of BRCA1-IRIS and thus WIP-1, prevented p53 and p38MAPK activation and their death.Results: This data suggest that BRCA1-IRIS is perhaps involved in the acquisition of cellular resistance to these agents upon prolonged exposure. On the other hand, depletion of BRCA1-IRIS from tumor cell lines induced apoptosis even in cells with functional p53 and p38MAPK.Discussion: We propose that in p53 wild type cells, whether endogenous or UV- or chemotherapy-induced BRCA1-IRIS overexpression leads to the survival and proliferation of what most likely are severely damaged cells, leading to the transformation of mammary cells in vitro and the induction of breast tumors in vivo. We also propose that BRCA1-IRIS and WIP1 overexpression abrogates the homeostatic balance maintained by p38-p53-WIP1 pathway. Together with the ability of BRCA1-IRIS to upregulate Cyclin D1 expression increases the likelihood that BRCA1-IRIS is an oncogene that induces breast cancer progression when overexpressed, hence making it an attractive target for novel breast cancer therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3154.