Identification of a gene signature that distinguishes estrogen-receptor positive from estrogen-receptor negative breast cancers may have potential value in predicting hormone therapy response.

4255 Estrogen receptor (ER) and progesterone receptor (PR) status are important factors in assessing breast cancer prognosis and treatment. Tumors which are ER positive (ER+) may initially respond to Tamoxifen anti-estrogen therapy, but often become hormone-independent. Although Tamoxifen significantly reduces tumor recurrence in certain patients with ER+ breast cancer, over time, approximately 40% of ER+ breast cancers will fail to respond or eventually develop resistance to Tamoxifen, leading to disease progression. Therefore, identification of a gene expression which could predict the response to Tamoxifen treatment would have important clinical application. Additionally, identification of genes involved in Tamoxifen resistance could provide important insights into biologic mechanisms of the non-responsiveness or aquired resistance. Using a cross-species microarray analytic approach, our lab has identified a signature of approximately 300 genes, highly predictive of the ER status of a human breast tumor. Futhermore, a subset of this signature was identified, which separated ER+ breast cancer patients into Tamoxifen responsive and Tamoxifen non-responsive groups. The expression of a set of developmentally regulated transcription factors within this signature are highly correlated with Tamoxifen treatment response or failure. A set of hoemebox genes are highly associated with ER+ status in human tumors. The roles of these genes in determining Tamoxifen response are being functionally tested in vitro by using siRNA and overexpression methods in Tamoxifen sensitive and resistant cell lines. The identification of this gene signature has potentially important implications for identifying ER+ breast cancer patients who may require additional forms of therapies since they will likely fail traditional anti-hormone treatment. Inhibition of specific genes in such tumors may be an important way to sensitize these tumors to hormone therapy.