Despite significant progress made during the past decade in elucidating important molecular mechanisms underlying breast and ovarian cancer, comprehensive knowledge about hypothesized multistep genetic alterations critical in their pathogenesis is lacking. In fact, only a fraction of putative molecular events hypothesized to be important in the common, sporadic malignancies arising from mammary and ovarian epithelial cells have been elucidated. Genome-wide comparative expression analyses and allelic imbalance analyses, as well as functional assays, of breast and ovarian cancers strongly suggest that alterations in additional, as-of-yet unidentified, genes may be critically important. A deeper understanding of the molecular mechanisms underlying tumor initiation and progression in these malignancies is urgently needed to facilitate innovative development of more effective diagnostic, prognostic, and therapeutic modalities to reduce significant disease associated morbidity and mortality. The goal of this proposal is to conclusively identify and functionally characterize a putative tumor suppressor gene important in breast and ovarian (BROV) cancer that we localized to a discrete, < 300 kb. interstitial region of chromosome 17g25. distinct from and distal to BRCA] . Our continued analyses have strongly supported the localization of a critically important BROV gene to this region. To date, we have developed a fine-scale allelic imbalance map, a comprehensive physical map, a partial transcript map, and an evolving genomic sequence map of the region surrounding a common overlapping discrete region of 17q25 loss in breast and ovarian tumors. We have begun analyzing transcripts and putative candidate genes. Interestingly, two genes mapping to the targeted region, MSF and SEC14LI, demonstrate some intriguing evidence suggesting they warrant continued investigation for their involvement in breast and/or ovarian malignancies. To further examine the relevance of these, as well as other, genes in relationship to 17q25 loss in human breast and ovarian cancers we will: 1) Complete a sequence rich detailed transcript map for this region refined by continued deletion mapping and functional assays, 2) Conduct mutational and expression analyses of attractive candidate genes in well-characterized breast and ovarian cancer cell lines and primary tumors, prioritizing further analyses of MSF and SEC14LI, 3) Perform in vitro and in vivo studies to help assess the function(s) of implicated candidate genes, 4) Create and examine appropriate knockout murine models, and/or targeted transgenic models with inactivating alterations, of the implicated 17q25 gene(s) as indicated.
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