(Adopted from the application)The cyclins and their catalytic partners, cyclin-dependent kineses (Cdks) are key regulators of the cell cycle. Overexpression of cyclin genes has been described in several forms of human cancers. Preliminary evidence suggests that cyclin E is expressed in a subset of gynecological cancers, namely clear cell carcinoma of the ovary, endometrium and cervix. The first specific aim will focus on confirming the specificity of cyclin E for clear cell tumors of Mullerian origin. Expression of cyclin E will be assessed in different histological subtypes of epithelial ovarian, endometrial, cervical and renal cancers. Cyclin E specificity for gynecologic clear cell carcinomas may provide a useful diagnostic marker to help distinguish a pelvic tumor of Mullerian versus non-Mullerian origin. This may have important implications in cases when the primary lesion is unknown since the therapy for ovarian and renal malignancies differs. Histological subtype specific aberrations in cyclin/Cdk expression may be important implications in the potential success of future therapies targeting Cdks. The first generation of these inhibitors are being evaluated in clinical trials. The second specific aim will evaluate steroid hormonal regulation of cyclin E using an in vitro model. The effects of estrogen and progesterone on cyclin E activity will be assessed using an ovarian cancer cell line. Increasing evidence suggests a role for hormones in the etiology of gynecologic malignancies. Moreover, cyclins have been shown to be regulated by estrogen and progesterone in breast cancer cell lines. The role of hormones in the development of reproductive tract cancer has important implications in the treatment of menopause and may also contribute to the direction of future therapeutic and preventative agents.
Specific aim three will evaluate the expression and activity of cyclin dependent kinase inhibitors in order to elucidate the mechanism of aberrant cyclin E activity. The activity of a cyclin/Cdk is dependent upon the association with cyclin dependent kinase inhibitors (CdkIs).
This specific aim will attempt to correlate cyclin E activity with the CdkIs, p2 1 and p27 in gynecologic malignancies. In addition, the role of estrogen and progesterone on CdkI association with cyclin E will be determined. Interestingly, it appears that the increase cyclin E activity in breast cancer cell lines in response to steroid hormones is mediated through alterations in the Cdk-inhibitory proteins. Understanding the mechanisms of cyclin E aberrations may lead to powerful and convenient models for studying potential tumor promoters, markers and antiproliferative agents.
