The Role of HMG-I/Y in Uterine Cancer

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DESCRIPTION (provided by applicant): Uterine cancer is the most common cancer of the female genital tract and the fourth most frequent cause for cancer death in women in the United States. The only available treatment is hysterectomy; there is no effective adjuvant therapy for this disease after it has spread outside the uterus. Thus, further study has the potential to significantly benefit women's health. Despite the high prevalence of this cancer, the molecular events that lead to neoplastic transformation in the uterus are poorly understood. In addition, there are limited animal models available to study these cancers. To better understand how uterine cancers develop, we are studying genes that contribute to its pathogenesis. Our focus is the HMG-I/Y gene because our preliminary studies suggest that it plays an important role in the development of uterine cancer. The HMG-I/Y gene encodes the HMG-I and - Y chromatin binding proteins, which function in regulating gene expression. Our pilot study shows that HMG-I mRNA and protein are up-regulated in high-grade human uterine cancers, but not low- grade cancers, benign tumors, or normal tissue. We also demonstrated that HMG-I and -Y have oncogenic properties in cultured cells. We recently generated transgenic mice that overexpress HMG-I in lymphoid tissue and all of them develop aggressive lymphoma. The transgene is also overexpressed in the uterus and all female mice develop uterine tumors with pathology resembling human uterine adenosarcoma. Thus, we hypothesize that HMG-I is an oncogene important in the pathogenesis of human uterine cancer. Our overall goal is to define the role of HMG-I in uterine cancer and begin to explore the mechanisms involved in transformation using unique reagents developed in my laboratory. Our Specific Aims are: 1.) Determine if HMG-I/Y can serve as a diagnostic marker for more aggressive uterine cancer. 2.) Determine if HMG-I/Y is necessary for transformation in uterine cancer cells. 3.) Begin to define the molecular pathways involved in H/WG-/-mediated transformation in uterine cancer using gene expression profile analysis. Results from these studies will enhance our understanding of uterine cancer and should ultimately lead to the development of better therapy. Relevance: Uterine cancer is a common and often incurable cancer that affects women worldwide. There is no effective therapy for this cancer after it has spread outside the uterus. Thus, research is urgently needed to determine how these cancers develop in order to design better therapies.