apc mutation enhances pymt-induced mammary tumorigenesisapc突变提高pymt-induced乳腺肿瘤发生.pdfVIP

Apc Mutation Enhances PyMT-Induced Mammary Tumorigenesis 1 2 2 1 Jenifer R. Prosperi , Andrey I. Khramtsov , Galina F. Khramtsova , Kathleen H. Goss * 1 Department of Surgery, University of Chicago, Chicago, Illinois, United States of America, 2 Department of Medicine, University of Chicago, Chicago, Illinois, United States of America Abstract The Adenomatous Polyposis Coli (APC) tumor suppressor gene is silenced by hypermethylation or mutated in up to 70% of human breast cancers. In mouse models, Apc mutation disrupts normal mammary development and predisposes to mammary tumor formation; however, the cooperation between APC and other mutations in breast tumorigenesis has not been studied. To test the hypothesis that loss of one copy of APC promotes oncogene-mediated mammary tumorigenesis, ApcMin/+ mice were crossed with the mouse mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) or MMTV-c-Neu transgenic mice. In the PyMT tumor model, the ApcMin/+ mutation significantly decreased survival and tumor latency, promoted a squamous adenocarcinoma phenotype, and enhanced tumor cell proliferation. In tumor-derived cell lines, the proliferative advantage was a result of increased FAK, Src and JNK signaling. These effects were specific to the PyMT model, as no changes were observed in MMTV-c-Neu mice carrying the ApcMin/+ mutation. Our data indicate that heterozygosity of Apc enhances tumor development in an oncogene-specific manner, providing evidence that APC- dependent pathways may be valuable therapeutic targets in breast cancer. Moreover, these preclinical model systems offer a platform for diss