Hormone Resistance and Progesterone Receptors in Breast Cancer

摘要

Our goal is to understand how breast cancers become resistant to hormone treatments. Study targets are the hormones, estradiol and progesterone; their antagonists, tamoxifen and RU486; and the receptors to which they all bind, estrogen (ER) and progesterone receptors (PR). There are two PRs -- the A- and B-isoforms. We created breast cancer cell models that express one or the other PR, and find that A- is inhibitory while B- is stimulatory. We address the paradox that progestins can stimulate growth of breast cancers, yet high doses successfully inhibit breast cancers. We discovered two proteins that interact with tamoxifen-occupie receptors, and alter the direction of transcription. The coactivator L7/SPA increases the agonist effects 0 tamoxifen but not estradiol. The corepressors NCoR and SMRT suppress the agonist activity of tamoxifen. We postulated that L7/SPA accelerates development of hormone resistance while the corepressors retard it. We tested this in a small cohort of tumors from tamoxifen sensitive or tamoxifen resistant patients. Initial studies indicate that corepressor levels are lower in resistant tumors, as predicted. Coactivators an corepressors could become predictive markers for tamoxifen resistance, and even therapeutic targets.