The PIK3CA gene is mutated in tumors from more than 25% of breast cancer patients, making the PIK3CA the most frequently mutated oncogene in breast cancer.To directly study the impact of somatic mutational activation of PI3K on breast tumorigenesis and to measure responses to PI3K-targeted therapies in vivo, we recently generated a transgenic mouse strain carrying the frequently occurring tumor allele, PIK3CAH1047R, under the control of a Tet-operator regulated promoter, coupled with IRES-Luciferase for in vivo imaging.By breeding the transgenie mouse with an MMTV-rtTA line, we have obtained an inducible system to conditionally express PIK3CAH1047R in the mammary epithelium of the bi-transgenic mice.The tumors arising in these animals following doxycycline induction have diverse and interesting phenotypes.While the transgene induction rapidly gives rise to hyperplasia in the breast ductal epithlium that is entirely dependent on transgene expression, more than 50% of tumors derived from prolonged transgene induction progress to a PIK3CAH1047R-independent state.Using array comparative genomic hybridization (aCGH)and affymetrix gene expression analyses, we identified a number of genetic alternations that are important players responsible for tumor escape from addiction to an initiating PIK3CA transgene.Finally, a potential new therapeutic intervention that overcomes the resistance to PI3K inhibition will be discussed.