Targeting Signaling Pathways for the Treatment and Prevention of Breast Cancer
Complex interaction of regulatory pathways known to participate in breast cancer tumorigenesis.
Our research is focused on critical endocrine pathways in human breast cancers regulated by nuclear hormone receptors that can be targeted for the treatment and prevention of breast cancer and other malignancies. RXR-selective retinoids (rexinoids) are promising candidates for the prevention of estrogen receptor (ER)-negative breast cancer, a disease not treatable by endocrine therapy. As these RXRs have been shown to be effective at minimal toxicity1, a better understanding of the underlying molecular mechanisms involved with RXR-mediated gene regulation and the development of more effective candidate therapeutic compounds for ER-negative breast cancer is necessary. We are currently investigating the role of RXR and its associated nuclear receptors as well as the role of cellular energy metabolism in regulating breast cell proliferation and transformation. Previously, we have described several mechanisms by which rexinoids regulate growth of pre-malignant mammary epithelial cells2. In addition, we have performed high throughput screens using RNAi to identify nuclear receptor partners of RXR essential for the growth regulatory effect of rexinoids, as well as kinase-dependent pathways of rexinoid resistance. We are currently using high-content cell-based assays, gene expression profiling and molecular techniques to discover additional pathways essential for growth regulation and elimination of pre-cancerous cells. It is our goal to identify effective chemopreventive agents that can be used at reduced dosage, and to determine synergistic combinations of those compounds to eliminate the long-term toxic side effects associated with these drugs.
- Uray IP, Shen Q, Seo HS, Kim H, Lamph WW, Bissonnette RP, Brown PH. Rexinoid-induced expression of IGFBP-6 requires RARbeta-dependent permissive cooperation of retinoid receptors and AP-1. J Biol Chem 284(1):345-353, 1/2009. e-Pub 10/2008. PMCID: PMC2610495.
- Uray IP, Brown PH. Chemoprevention of Hormone Receptor-negative Breast Cancer: New Approaches Needed. Recent Results Cancer Res 188:147-62, 2011. PMID: 21253797.
Lab members working on this project: