Abstract P1-05-06: Essential role of notch-4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is process in which epithelial cells undergo unique morphologic changes characterized by a transition from epithelial cobblestone phenotype to elongated fibroblastic phenotype (mesenchymal phenotype) leading to increased motility and invasion. Our previous study demonstrated that tamoxifen (TAM)-resistant human breast cancer (TAMR-MCF-7) cells showed the increased expression of mesenchymal marker proteins compared to the parent MCF-7 cells. Notch plays a crucial role in the promotion of EMT during both development and tumor progression. Especially, Notch-1 and Notch-4 were reported as prognostic markers in human breast cancer. Here, we found that the basal expression and activity of Notch-4 were significantly increased in TAMR-MCF-7 cells compared to control MCF-7 cells. Suppression of Notch-4 by either Notch inhibitors or Notch-4 siRNA significantly attenuated the EMT signaling. Interestingly, long-term treatment with DAPT, a Notch inhibitor, eventually led to partial reversal of EMT by up-regulating E-cadherin expression. Activated or tyrosine-phosphorylated STAT3 (pYSTAT3) protein is supposed as a critical signaling molecule in the regulation of tumorigenesis and metastasis of cancer cells. We further found that TAMR-MCF-7 cells exhibited constitutive STAT3 phosphorylation. Suppression of Notch-4 activation attenuated the activated STAT3 elevation in TAMR-MCF-7 cells. We hypothesized that Notch-4 regulated EMT in TAMR-MCF-7 cells via STAT3 signaling. Intrasplenic injection model of liver metastases was performed using TAMR-MCF-7 cells. Mice were received subcutaneous injections daily with DAPT (10 mg/kg) formed smaller tumor size in spleens and showed less micrometastatic tumor burden in livers compared to group treated with vehicle. In conclusion, inhibition of Notch signaling may have efficacy in the treatment of breast cancer metastasis. Citation Format: Bui QT, Kang KW. Essential role of notch-4/STAT3 signaling in epithelial-mesenchymal transition of tamoxifen-resistant human breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-05-06.