Ovarian epithelial tumors are subdivided into design (cystadenomas) and malignant (carcinomas) categories. There is also an intermediate entity known as tumors of low malignant potential (LMP). The principal investigator's previous grant focused on identifying frequent molecular genetic differences between these different tumor subtypes in order to obtain insights into the molecular determinants for their phenotypic differences. Recently, the principal investigator's laboratory has succeeded in immortalizing several ovarian cystadenoma cell lines in culture as well as a cell line derived from a LMP tumor. The principal investigator now proposes to pursue studies directed at understanding the molecular genetic determinants of ovarian epithelial tumor development by taking advantage of the above-mentioned cell lines to address the functional significance of specific molecular alterations.
Three specific aims are proposed.
The first aim will examine the functional significance of expression of steroid and gonadotropin hormone receptors. The levels of expression of such receptors vary among different ovarian tumors and the significance of those differences as well as the potential role of hormone therapy in the management of these tumors is presently unclear. The second specific aim is based on findings from the first grant period that losses of heterozygosity are frequent molecular genetic abnormalities in ovarian carcinomas but are apparently absent in cystadenomas. The principal investigator proposes that the 2 groups of ovarian tumors develop via fundamentally distinct mechanisms and that the presence of loss of heterozygosity, which he regards as a measure of aneuploidy, strongly predisposes to malignant development. The principal investigator will test this hypothesis using 2 different approaches to create mitotic errors in cultured cystadenomas. Such mitotic errors are expected to result in aneuploidy and loss of heterozygosity. The rate of malignant transformation will be compared in treated and control cells. Finally, in the third specific aim, the principal investigator will pursue his recent findings suggesting that a gene which may escape X chromosome inactivation is important for the control of ovarian LMP tumors. This candidate gene will be further localized on the X chromosome and a function for its role in ovarian tumorigenesis may be ascribed to it using microcell-mediated chromosome transfer technologies.
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