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.
|Effective start/end date||8/1/13 → 7/31/14|