Genetic polymorphisms of calcium channel in the risk of breast cancer

Breast cancer is the most common female malignancy with an increasing number of new cases around the world. Previous results have indicated that calcium entry through store-operated calcium channel can trigger breast cancer cell metastasis. Clinical evidences suggested expression of membrane HER2, and COX-2, could be used to predict poor disease-free survival in patients on endocrine treatment (Tamoxifen). Our preliminary data indicated that one SNP in store-operated calcium channel has significant association with the distal metastasis in the breast cancer patients. In addition, Tamoxifen could somehow induce COX-2 gene expression. For systematically discovering the genetic polymorphism effects of calcium channel in the development of breast cancer and Tamoxifen -mediated signaling pathways, we will mainly focus on ORAI1, an essential unit of store-operated calcium channel and STIM1, a calcium sensor, for performing a genetic case control study in the Taiwanese population. The correlation between the genotypes and therapeutic outcomes will also be identified. To explore mechanisms of how Tamoxifen-mediated COX-2 activation, both physiological and genetic approaches will be applied. The specific aims of this project are (1) To determine the association between the genetic polymorphisms of ORAI1/STIM1 and the risk of breast cancer (2) To explore novel cellular signaling pathways for Tamoxifen-mediated COX-2 expression. This proposal addresses a novel mechanism of inflammatory gene as well as calcium signaling evoked by Tamoxifen. By identifying how Tamoxifen stimulation activates calcium mobilization and COX-2 gene, these findings will set up a new regulatory pathway for the pharmacological relevance of Tamoxifen. By using case-control study, we also expect to find out the association between genotypes of ORAI1/STIM1 and the pathogenesis of breast cancer. These results should provide new molecular insight into the composition of the ion channels as well as identifying a key genetic marker for pharmacological control of breast cancer.