Uncontrolled proliferation is a hallmark of cancer. Transforming growth factor-beta (TGF-beta) is one of a few known endogenous inhibitors of cell growth. Therefore, our studies have centered on why this ubiquitously expressed protein does not harness the growth of cancer cells, in vivo. TGF-beta inhibits cell proliferation by directly effecting genes/proteins that control the cell cycle causing growth arrest in late G1 phase. In hormonal carcinogenesis, hormone action can affect both growth stimulation (e.g., estrogens, androgens) and inhibition (e.g., progesterone) through interactions between hormones and growth factors and epithelial and stromal cells composing hormone-regulated tissues/organs. We have developed physiological model systems to dissect these interactions and signaling pathways in hormone-dependent endometrial and prostate cancer growth including, purified normal and malignant cells derived directly from excised tissue, co-cultures of the stromal and epithelial cells, organ cultures, and mouse and human endometrial cells combined to re-form heterospecific tissue (in diagram below). In the latter, hormone receptor null mouse endometrial cells are used to determine the cell-type specific hormone responses. Further, co-cultures of epithelial and stromal cells are used to determine the soluble mediators involved in hormone-induced growth regulation. It is interesting that stromal cells adjacent to carcinoma cells demonstrate aberrant behavior and can stimulate growth of normal epithelial cells. Our recent studies have shown that disruption of TGF-beta signaling is an early event in endometrial carcinogenesis causing loss of (TGF-?r-mediated) growth inhibition of the carcinoma cells. Specifically, TGF-beta receptors are down-regulated (lost) and the post-receptor signaling protein/transcription factor, Smad, is not activated/functional. Accordingly, downstream to TGF-beta signaling, the cyclin-dependent kinase inhibitors (cki) of the cell cycle, p27kip1 and p15, are concomitantly lost/decreased thereby permitting proliferation. Further studies will focus on understanding how TGF-beta receptors are downregulated (eg. methylation), how the levels of the cki, p27 are post-translationally controlled by TGF-beta(e.g. via the ubiquitin-proteasome pathway), and how gonadal hormones regulate both, normal and malignant growth by specific growth factor elaboration and stromal/epithelial interactions. Our ultimate goal is to define molecular targets that can be translated into treatments for cancer prevention and therapy.

We also study molecular pathogenesis related to wound repair, inflammation and fibrosis and structure/function relationships of fibronectin. We are particulalry interested in the molecular structures that compose fibronectin binding sites for fibrin, heparin, and immunoglobulin and in the biochemical characterization of these binding interactions. The interaction of fibronectin with fibrin is important in fibrin clot formation in wound repair and vascular disease and we have proposed that the interaction of fibronectin with immunoglobulins may play a role in the pathophysiology of immune complex disease.