A Transposon-based Analysis Reveals <i>RASA1</i> Is Involved in Triple-Negative Breast Cancer.

Abstract

RAS genes are mutated in 20% of human tumors, but these mutations are very rare in breast cancer. Here, we used a mouse model to generate tumors upon activation of a mutagenic T2Onc2 transposon via expression of a transposase driven by the keratin K5 promoter in a p53^+/- background. These animals mainly developed mammary tumors, most of which had transposon insertions in one of two RASGAP genes, neurofibromin1 (<i>Nf1</i>) and RAS p21 protein activator (<i>Rasa1</i>). Immunohistochemical analysis of a collection of human breast tumors confirmed that low expression of RASA1 is frequent in basal (triple-negative) and estrogen receptor negative tumors. Bioinformatic analysis of human breast tumors in The Cancer Genome Atlas database showed that although <i>RASA1</i> mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with <i>TP53</i> mutation. Inactivation of <i>RASA1</i> in MCF10A cells resulted in the appearance of a malignant phenotype in the context of mutated p53. Our results suggest that alterations in the Ras pathway due to the loss of negative regulators of RAS may be a common event in basal breast cancer. <i>Cancer Res; 77(6); 1357-68. ©2017 AACR</i>.