Biography

My lab focuses on the plasma membrane estrogen receptor (ER) and its effects on the biology of estrogen action. This includes both in-vitro and in-vivo models. Our work always stems from a clinically important observation in humans that is mechanistically not understood. The focus currently is on 1) estrogen action to promote breast cancer development, and 2) the anti-hypertrophy effects of estrogen on the cardiomyocyte. As part of the studies, we are trying to understand the molecular structure /function aspects of the membrane estrogen receptor, that allows for signaling, and membrane localization. These studies involve mutagenesis or inhibition of endogenous receptors, and genetic mouse models (ERalpha selective cell pool knockout).A focus on mitochondrial ER is also important in the lab, underlying tamoxifen sensitivity versus resistance in breast cancer.

Estrogen use after the menopause leads to increased risk of breast cancer. We have shown that this results from both increased proliferation of breast cancer cells and increased survival. In fact, tamoxifen, taxol or radiation treatment of breast cancer causes apoptosis, and we showed that estrogen prevents this. Both proliferation and survival effects of ER are importantly mediated through signaling to ERK MAP kinase via the membrane ER. This leads to detailed cell cycle events, and anti-apoptotic events that we have delineated. Important cell cyle events involving proliferation include estrogen-induced cyclins B and D1 proteins, and cdk4 and cdc2 activation. Signaling from the membrane ER requires cross-activation of the membrane EGF receptor, and we have published many of the details of this cross-talk between G-protein coupled ER and the tyrosine kinase EGFR. Our most recent work has defined the nature of the enzymes that plamitoylate ER and drive it to the plasma membrane. Recent work has focused on the pleuri-potent bone marrow-derived stem cell and how various cellular pools of ER collaborate to suppress commitment to adipogenesis.

We also recently found that estrogen protects cardiomyocytes against the development of hypertrophy, which fits with human studies showing protection by estrogen against the development of heart failure. The mechanisms and genes involved are being delineated using DNA array, siRNA and other approaches, in-vitro and in-vivo.

Research Interest