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 (Nf1) and RAS p21 protein activator (Rasa1). 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 RASA1 mutations are rare, allelic loss is frequent, particularly in basal tumors (80%) and in association with TP53 mutation. Inactivation of RASA1 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. Cancer Res; 77(6); 1357-68. ©2017 AACR.
Highlights
Ras genes are some of the most frequently mutated in human cancer
Keratin K5 is expressed in the myoepithelial layer of the mammary gland, and SB11 transposase was detected in this layer of transgenic animals (Fig. 1D)
Our screen has identified a number of gene-centric Common Insertion Site (gCIS) that are known to function as tumor suppressor genes and are subject to loss-of-function mutations in human breast cancer
Summary
Ras genes are some of the most frequently mutated in human cancer. According to the catalog of somatic mutations in cancer 1), which represents the most comprehensive database on human cancer mutations currently available, around 20% of the analyzed tumors have activating mutations in any of the 3 Ras genes, with a maximum of 57% incidence for KRAS in pancreatic tumors. Ras signaling may be activated by other means, notably by inactivation of molecules that limit Ras activity, such as Ras GTPase-activating proteins (RasGAP). Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). C. Suarez-Cabrera and R.M. Quintana contributed to this study
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