The long-term objectives of this project are to understand the relationships among several prominent factors in female genital carcinogenesis: downregulation of cell-cell adhesion components; steroid hormone treatment; and upregulation of epidermal growth (EGF) factor. Cadherins play an important role in the controlled proliferation and differentiation of normal epithelial tissues. Down-regulation of cadherins has been correlated with the development of several types of cancers. A better understanding of the means by which cadherins are down-regulated will help in establishing the course of action taken in the treatment and prevention of female genital carcinomas.
The specific aims of this proposal focus on regulation of cadherins by steroid hormones and the relationship between steroid regulation of cadherins and overexpression of EGF receptor in the vulvar-carcinoma derived cell line, A431, and in other female genital carcinoma-derived cell lines. Specifically this application proposes to: 1. Establish whether dexamethasone regulation of cadherin expression is unique to A431 cells or occurs in other squamous carcinoma-derived cell lines. 2. Determine if steroids other than dexamethasone are capable of regulating cadherin expression in female genital carcinoma-derived cell lines. 3. Establish whether dexamethasone regulation of cadherin expression in A431 cells is dependent on overexpression of EGF receptor. The effect of dexamethasone on cadherin expression will be examined in cell lines derived from other squamous-cell carcinomas, with particular emphasis on examining cell lines derived from female genital carcinomas. In addition to dexamethasone, estrogen, progesterone or a combination of estrogen and progesterone will be examined for their effect on cadherin regulation in genital carcinoma-derived cell lines. To examine the relationship between EGF receptor overexpression and dexamethasone regulation of cadherins, the applicant will develop clones of A431 cells which are resistant to EGF or have inactive EGF receptor, and will examine these cells for dexamethasone-inducible down-regulation of cadherins. In addition, cell lines, which do not down-regulate cadherin expression with dexamethasone treatment and do not overexpress EGF receptor, but grow in the presence of dexamethasone, will be transfected with an EGF receptor construct designed to overexpress the EGF receptor in these cells. The transfectants will then be tested for down-regulation of cadherins in response to dexamethasone.
