Richard J. Santen, MD
Estrogen regulated control of proliferation and differentiationof hormone dependent breast cancer; nongenomic and genotoxic effects of estrogen
One project examines the role of adaptive hypersensitivity in the re-growth of hormone dependent breast cancer following initial hormonal therapy and focuses on mechanisms up-stream of the cell cycle. The goals are to determine how the adaptive process modulates receptor functionality, growth factor pathways, estrogen metabolism, and interactions among these various factors. A major emphasis is the evaluation of non-genomic effects of estradiol acting on plasma membrane related estrogen receptors. This project examines the role of SHC, Grb-2, SOS and cSRC in mediating non-genomic effects of ER. Designer cells are used to determine what regulates the localization of ER alpha in the plasma membrane. This grant examines whether growth factor activation represents an increase in ligand production or constitutive receptor activation. Cell lines with up-regulation of MAP kinase, Raf, EGF-R, and Erb-B2 are used as models to asses the mechanistic effects of these pathways on estradiol induced cell proliferation. To characterize ER-mediated non-genomic effects, these studies use dominant negative constructs and inhibitors to directly examine the effects c-SRC and SHC on cell proliferation. This project also examines the role of co-activators and co-repressors of ER on receptor functionality.
Another project examines the formation of depurinating catechol-estrogen-DNA adducts in breast tissues of the aromatase over-expressing transgenic mouse. The goals are to examine whether the aromatized products of androgen can be converted into genotoxic metabolites and cause neoplastic changes in benign breast tissue. Serial transplantation using the hyperplastic alveolar nodule (HAN) model is used to prolong the exposure of breast tissue to endogenously formed genotoxic metabolites. The project determines whether aromatase inhibitors prevent the formation of genotoxic metabolites of estradiol and the development of breast hyperplasia and neoplasia. These studies examine the factors downstream of the estrogen receptor which mediate adaptive hypersensitivity to estradiol.
Another project evaluates the role of the E2F transcription factors and cyclin E in the regulation of estradiol induced proliferation. It examines the effects of the cyclin inhibitors of the INK 4a-d group as well as the Cip-1/Waf-1/Kip1/Kip2 families on hormone induced cell growth. The effects of growth factors on E2F production and function in combination with steroid hormones are examined. Finally, the role of estrogens on the process of cell death are evaluated. The ultimate goal of this grant is to find out how breast cancer cells adapt to hormonal therapy and respond sequentially to multiple endocrine therapies before becoming totally resistant to these maneuvers.
Another project examines the effects of FTS (farnesylthiosalicylic acid) on the growth of breast tumors that have upregulated the MAP kinase and PI 3 kinase pathways. They have recently shown that this drug inhibits mTOR through a unique mechanism to disrupt the binding of mTOR to raptor. They are now determining whether this drug blocks the binding of Rheb to raptor as a potential mechanism of action. They collaborate with Peggy Shupnik and with John Lawrence.