Mechanisms of estrogen and aromatase action breast cancer initiation and progression, and development of therapeutic strategies for hormone-dependent breast cancer

The Yue laboratory focuses their study on the mechanisms of estrogen in breast cancer initiation and progression, and development of therapeutic strategy for hormone-dependent breast cancer. To study metabolite mediated carcinogenic effect of estradiol, an in vitro MCF-10A (benign breast epithelial cell line) overexpressing aromatase was established. It was demonstrated that overexpression of aromatase increases estrogen production in situ and the levels of genotoxic estrogen metabolites. More importantly aromatase overexpression rendered the cells ability to grow in soft agar. To further demonstrate the carcinogenic effect of estradiol, a mouse model with estrogen receptor ? knocked-out and Wnt-1 transgene was used to segregate receptor- and metabolite-mediated actions of estrogen. It has shown that estradiol dose-dependently increases mammary tumor incidence in the absence of ER?. These results provide experimental evidence on superiority of aromatase inhibitors to antiestrogen in prevention of breast cancer because the former will block both receptor- and metabolite-mediated effects of estrogen.

Hormone-dependent breast cancers uniformly relapse 12-18 months after primary endocrine therapy. Enhanced Interaction between estrogen receptor and growth factor pathways is an important mechanism for escape of breast cancer cells from estrogen deprivation and re-growth. It is demonstrated in this lab that the MAP kinase and the PI3K/mTOR pathways play important role in proliferation of MCF-7 breast cancer cells after a long-term estrogen deprivation. Recently, the lab in collaboration with Dr. John Lawrence uncovered a novel mechanism of the antitumor effect of farnesylthiosalicylic acid (FTS, a putative anti-ras agent). This drug exerts more potent inhibitory effect on mTOR activity than on MAP kinase and significantly inhibits growth of breast cancer cells. This collaboration with Dr. Lawrence led to two publications (Mol. Endocrinol. 19:175-183, 2005; Int. J. Cancer in press). All above projects are pursued in collaboration with Dr. Richard Santen.