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From flies to humans combining whole genome screens and tissue specific gene targeting to identify novel pathways involved in cancer and metastases

Final Report Summary - COMBINE (From flies to humans combining whole genome screens and tissue specific gene targeting to identify novel pathways involved in cancer and metastases)

Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. A primary goal of our team was to generate a platform for the development and application of functional genomics in order to understand the pathogenesis of malignancies and to provide novel models to test and possibly develop cutting edge therapies. To accomplish this, we integrated our expertise with tissue-specific in vivo RNAi in Drosophila with human tumor profiling and functional mouse genetics to identify novel pathways for cancer pathogenesis.

Using gene-targeted mice, our group has previously identified RANKL as the master gene of bone loss in arthritis and osteoporosis, mammary gland development in pregnancy, and cancer cell migration into bone. Since RANKL is regulated by sex hormones and controls mammary epithelial cell proliferation during pregnancy, we developed the hypothesis that RANKL and its receptor RANK could be involved in the initiation of primary breast cancer. We therefore developed genetic tools to selectively delete RANK in mammary epithelial cells. We were able to show that synthetic progesterone derivatives such as MPA, still used in millions of women for hormonal replacement therapy and contraception, massively induce RANKL in the mammary gland and that RANKL/RANK mediate sex hormone driven breast cancer. We proposed a molecular model how progestins drive mammary cancer: MPA triggers induction of RANKL in the mammary gland, which through RANK drives mammary epithelial progenitors cells into the cell cycle and protects them from apoptosis in response to DNA damage. Moreover, the RANKL/RANK system controls self-renewal of tumor inducing stem cells. Thus, the progestin-induced RANKL/RANK system provides a growth and survival advantage to damaged mammary epithelium, a prerequisite to the initiation of mammary cancer. Our paper (Schramek et al. 2010) was published back-to-back with a study by Bill Dougell (Gonzalez-Suarez et al. Nature 2010), who showed that therapeutic inhibition of RANKL reduced the incidence of sex hormone (MPA/DMBA)-driven mammary adenocarcinomas from 100 to about 10% incidence of developing. Since our results show that the RANKL/RANK system is an important molecular link between progestins and epithelial carcinogenesis, we proposed that RANKL inhibition should be considered as a novel approach to the prevention and/or treatment of breast cancer. We continued to explore the cross talk of RANKL/RANK to other cancer inducing system, in particular BRCA1 mutations. Whether RANKL inhibition can be indeed used for prevention of breast cancer, as predicted from mouse studies, now needs to be determined in clinical trials.

To identify conserved genetic networks involved in Ras-driven tumorigenesis and metastases, we performed a large scale epithelial specific RNA interference (RNAi) screen in Drosophila.
We identified hundreds of novel candidate genes that might play a role in epithelial tumor progression and metastases. To address the question whether the genes identified in our Drosophila tumor screen can be directly translated to human cancer, we compared mRNA expression levels of the corresponding human orthologs in 3351 human primary cancers. These data allowed us to generate a global network map of RasV12-driven tumorigenesis. Multiple fly candidate genes are currently being investigated using gene targeting of candidate cancer genes in mice. Our results ranging from large scale functional fly screens to human patients and in vivo mouse tumor growth/metastasis experiments show that functional genetic networks controlling tumor growth and invasion appear to be evolutionary conserved. We have thus identified multiple novel candidate tumor suppressors and cancer modifiers.