Abstract SY36-04: Analysis of autophagy functions in mouse models of breast cancer

Abstract

Abstract Autophagy is a conserved bulk protein and cytoplasm degradation mechanism that plays crucial roles in many biological and diseases processes including cancer. Previous studies suggested that autophagy could function as a tumor suppression mechanism because mutations in autophagy gene beclin1 were associated several human cancers and also lead to spontaneous malignancies in mice. However, other studies using cancer cell lines and mouse xenograft models also suggested pro-tumorigenesis functions of autophagy in various cancers. FIP200 (FAK-family interacting protein of 200 kDa) was initially identified in our lab as a protein that interacts with and inhibits the kinases Pyk2 and FAK. Subsequent studies showed that FIP200 also associates with other cellular proteins and regulates several signaling pathways. In particular, recent data from several groups identified FIP200 as the mammalian counterpart of yeast Atg17 in the ULKs-Atg13-FIP200 complex essential for autophagy initiation in mammalian cells. To investigate the role of autophagy in spontaneous tumors developed in animals with intact immune system, we created germline and conditional knockout (KO) of FIP200 gene in wild type mice or the well-characterized MMTV-PyMT mouse model of human breast cancer. We found that heterozygous deletion of FIP200 did not lead to development of mammary or any other tumors, whereas homozygous deletion resulted in embryonic lethality. Moreover, conditional KO of FIP200 in mammary epithelial cells did not lead to spontaneous development of breast cancer either, suggesting that unlike beclin 1, FIP200 did not function as a suppressor for breast cancer in vivo. Surprisingly, we found that suppression of autophagy by FIP200 inactivation inhibited mammary tumorigenesis and progression in animals with intact immune system. Further studies showed that mammary tumor cells isolated the mutant mice exhibited significantly decreased proliferation in vitro, suggesting that intrinsic defect of proliferation in FIP200-null tumor cells contributes at least in part to the suppressed mammary tumor development in vivo. In addition, gene profile analysis revealed significantly elevated expression of interferon-gamma responsive genes in the tumors of FIP200 conditional KO mice. Furthermore, we observed an increased infiltration of effector T cells in the tumor microenvironment of these mice triggered by an increased production of chemokines including CXCL10 in FIP200-null tumor cells. Together, these studies demonstrate a pro-tumorigenic function of autophagy by promoting tumor cell proliferation and controlling host immune response, and also suggest FIP200 or other essential autophagy proteins as potential targets for cancer therapy. This research was supported by NIH grant CA150926. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY36-04. doi:1538-7445.AM2012-SY36-04