The Molecular Biology of Steroid Hormone Action
The effects of steroid hormones, such as estrogens, testosterone and other androgens, thyroid hormone, retinoids, Vitamins A and D, bile acids and oxygenated cholesterol derivatives are mediated by binding of these small molecules to specific receptor proteins called steroid/nuclear receptors. This large-superfamily of gene regulatory proteins represents the fundamental system for ligand-regulated gene transcription in multicellular eukaryotes.
Estrogen and Androgen-dependent Breast and Prostate Cancer
In addition to their roles in growth and differentiation in normal cells, steroid hormones play critical roles in cancer and other human diseases. Acting through the estrogen receptor (ER), estrogens play a key role in the growth and metastases of most human breast cancers. Testosterone, acting through the androgen receptor (AR), plays a key role in growth of both primary and recurrent prostate cancers. Treatment of breast and prostate cancer involves inhibiting hormone production and the use of small molecules, such as tamoxifen, that compete with the normal hormones for binding to the receptor. Although effective initially, the tumors eventually develop resistance to these therapies and the tumors return and resume growth. Breast and prostate cancer currently kill ~42,000 and ~23,000 Americans each year, respectively. An important goal of our research is to identify new small molecule inhibitors of ER and AR action in breast and prostate cancer that bypass the site targeted by current drugs and are effective against tumors that are resistant to current therapies.
Our Research:
A few years ago, we decided to leverage our expertise in receptor-DNA interaction by developing a new platform that would allow rapid screening of small molecules for their ability to inhibit binding of proteins to their DNA (and RNA) recognition sequences. Because of its ability to rapidly analyze macromolecular interactions in real-time, this system has also been a powerful new research tool. Today, our research includes drug discovery efforts focused on the development of new drugs for estrogen-dependent breast cancers and androgen-dependent prostate cancers and fundamental research on mechanisms of steroid receptor action.