Endometrial cancer is the most common gynecologic malignancy in developed countries, with approximately 39,000 new diagnoses and over 6000 deaths occurring annually in the United States. However, despite the evident risks to women's health, the molecular mechanisms underlying the onset and progression of endometrial tumors are poorly understood. Apoptosis, or programmed cell death, occurs during normal growth and development and in a variety of diseased states. Aberrant apoptosis is thought to contribute to the pathology, onset and progression of cancer and is associated with resistance to chemotherapy. In the endometrium, alterations in apoptosis have been implicated in both abnormal ovarian/menstrual cycling and endometrial hyperplasia and carcinoma. Increasing apoptotic index correlates with disease progression from atypia to malignancy and high levels of apoptosis are associated with more aggressive, higher-grade tumors with poorer patient prognosis. Endometrial cancers also exhibit alterations in the expression profile or activities of members of the Protein Kinase C (PKC) family, compared to normal tissue and aberrant levels or activation of specific PKC isoforms are postulated to contribute to endometrial neoplasia and transformation. Since PKCs are important regulators of both cell growth and apoptosis in many cell types, we hypothesize that these two characteristic of endometrial tumors are mechanistically linked and that select PKC isoforms differentially regulate apoptosis, survival and proliferation in the endometrium and are critical factors in the formation and progression of endometrial cancers. Adenoviral constructs encoding active or inhibitory PKC isoforms will be used to determine the functional role of specific PKCs in the regulation of apoptosis, growth, migration and invasion in endometrial cancer cells. Changes in PKC expression, localization and/or activity, induced by apoptosis, will be examined and potential upstream regulators or downstream targets of PKC in the apoptotic pathway identified and characterized. Finally, stable cell lines constitutively or inducibly expressing PKC constructs will be used in a mouse xenograft model to elucidate the functional role of PKC isoforms in the growth or regression of endometrial tumors in vivo. Understanding the function and molecular targets of specific PKCs in endometrial cancer will demonstrate their potential as prognostic or diagnostic indicators to identify aggressive, malignant, metastatic tumors and may provide novel strategies for therapeutic intervention. ? ?
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