XIST RNA and Ovarian Cancer

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DESCRIPTION (provided by applicant): XIST is a gene within the region on X chromosome known to contain the X inactivation center and is unique in being expressed exclusively from the inactive X chromosome. Gene disruption and cDNA transgene experiments have shown that XIST is both necessary and sufficient for X inactivation. The product of XIST is a large noncoding RNA that remains associated with the inactive X chromosome in female nuclei. However, the mechanism of XIST-mediated gene inactivation is largely unknown. By cDNA microarray expression analysis of paired primary and recurrent tumors from the same ovarian cancer patient we have identified XIST as the most differentially expressed gene that is down-regulated in the recurrent tumor. Subsequent analysis of XIST in a panel of ovarian cancer cell lines and ovarian cancer cases has shown that XIST expression is significantly correlated with cellular sensitivity to Taxol and relapse-free period of the patients. Recent studies have also revealed a specific function of the breast and ovarian tumor suppressor protein BRCA1 in supporting XIST RNA localization to the inactive X chromosome and probably in gene silencing. Inhibition of BRCA1 synthesis led to loss of focal XIST staining and increased expression of an otherwise silenced marker gene located on inactive X chromosome. We hypothesize that the interaction between BRCA1 and XIST RNA may play a significant role in affecting the expression of X-linked genes and chemosensitivity in ovarian cancer as well. The specific aims of this proposal are: 1. To characterize the relationship between BRCA1, XIST RNA, X inactivation status, and drug sensitivity in ovarian cancer cell lines; 2. To investigate if alterations of BRCA1 and XIST RNA expression can change the X inactivation status and chemoresponse of the cancer cell lines; and 3. To evaluate XIST and other variables in ovarian tumor samples. It is expected that these studies may provide insights into the relationship between XIST and BRCA1 in X inactivation process and probably in affecting drug response. Elucidating the mechanism underlying these two processes and identification of downstream targets may have significant implications in clinical management and development of strategy in treating ovarian cancer patients with chemotherapy.