Cellular and Molecular Mechanisms of Estrogen-Dependent Proliferation, Breast Cancer Development and Progression

Estrogen is a key factor in the development and function of the mammary gland. Exposure to estrogen is a well known risk factor for breast cancer. For this reason, prevention and treatment of breast cancer can be mediated by the use of antiestrogens, such as tamoxifen, that block tumor growth. The main interest of the lab is to understand the mechanisms by which estrogens control normal mammary gland proliferation and tumor development. In addition, we are interested in determining the molecular mechanisms that allow progression of breast cancer to tamoxifen resistance. We consider these mechanisms important to unravel as they may allow us to design new therapeutic strategies for breast cancer treatment and/or prevention.

One major focus of the lab is to understand how estrogen controls the proliferation of breast cancer cells. Estrogen regulates the expression and activity of G1 cyclins leading to rapid phosphorylation of the retinoblastoma protein. Specifically, it induces expression of cyclin D1 and cyclin D1-cdk4 kinase activity followed by activation of cyclin E-cdk2 complexes. We have been able to determine the molecular events necessary for estrogen-dependent cyclin E-cdk2 activation. At this point we still do not know the molecular pathways that are involved in estrogen-dependent cyclin D1 expression. We are currently characterizing the ability of different molecules that interact with the estrogen receptor to interact with this pathway.

Another area of research in the lab is to evaluate if the direct effect of estrogen on the cell cycle is a normal estrogen response or has been acquired during the process of tumorigenesis. Therefore, we are studying the effects of estrogen in the proliferation of normal human mammary epithelial cells. We hope these studies will allow us to discern if the ability of estrogen to drive cell proliferation in a cell autonomous way is acquired during the process of tumor development. If estrogen effects are different between breast cancer cells and normal mammary epithelial cells we would like to determine what are the changes in breast cancer cells that lead to this switch in the signal tranduction pathway regulating estrogen receptor function.

Recently tamoxifen has been shown to be an effective preventive agent. However, the tumors that appear in a person taking tamoxifen as a preventive agent most likely will be resistant to this antiestrogen. We are also interested in understanding the molecular mechanisms that lead to tamoxifen resistance. Some of the molecules that may allow breast cancer cells to grow in the presence of antiestrogen may be targets for the design of new pharmacological therapies.