Identification of Two Candidate Tumor Suppressor Genes on Chromosome 17p13.3: Assessment of Their Roles in Breast and Ovarian Carcinogenesis
Final rept. 1 Jul 1996-30 Jun 2001
FOX CHASE CANCER CENTER PHILADELPHIA PA
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OVCA1 and OVCA2 were first identified by us as candidate tumor suppressor genes, due to the fact that they map to a critical region of frequent allelic loss in breast and ovarian cancer at l7p13.3. Our studies have shown that OVCA1 is mutated in some tumor cell lines, and its protein levels are decreased or lost in nearly 40 of breast and ovarian adenocarcinomas, while OVCA2 appears to be unaffected. Expression of low levels of exogenous OVCA1 results in dramatic growth suppression and decreased levels of cyclin D1. We used a yeast-2-hybrid screen to identify OVCA1-associating proteins. One such protein, RBM8, was identified. Amino acid sequence indicates that RBM8 is a new member of an RNA-binding motif RBM family which is highly conserved evolutionarily. RBM8, also know as Y14 has been shown to be a shuttling protein that preferentially associates with spliced mRNA in the nucleus and remains associated with newly exported mRNA in the cytoplasm. Mutational analysis revealed no somatic mutations in ovarian tumor however, our current studies suggest that RBM8 is involved in mRNA export and that its levels may be significantly upregulated in most transformed cells. Overall, our studies indicate that altered expression andor post-translational modifications of OVCA1 is associated with the development of breast and ovarian tumors and suggest a potentially new mechanism for the inactivation of tumor suppressors in cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research