Abstract 548: CXCR2 controls breast cancer metastasis and chemoresistance through PI3K/AKT and COX-2 signalings.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Breast cancer is the chief culprit leading to woman's death. The major cause is the chemoresistance and distant metastasis before or after surgery and standard treatment. Recent studies suggest that chemokines and their receptors may play important roles in breast cancer metastasis and chemoresistance. Purpose: The chemokine receptor CXCR2 is associated with tumor development in many cancers. Although IL-8 and Gro-alpha as the major ligands contribute to breast cancer progression, the function of their receptor CXCR2 in breast cancer is elusive. In this study, we investigated the role of CXCR2 in breast cancer metastasis and chemoresistance. Experimental design:Human breast cancer cell lines including MCF-7 and SKBR-3 (low metastasis), MDA-MB-231 (medium metastasis), MDA-MB-231HM (high lung metastasis), MDA-MB-231BO (high bone metastasis), and MDA-MB-231/Gem (Gemcitabine-resistant) were used to investigate cell proliferation, migration, invasion, colony formation, apoptosis, and tumorigenesis by MTT, scratch-wound, transwell, soft agar, flow cytometery, and animal assays after CXCR2 or its associated proteins were over expressed or silenced/inhibited. Protein expression in cell lines and tissues was examined by either Western blot, ELISA, immunofluorescence, or immunohistochemical staining. Results: CXCR2 expression was higher in chemoresistant breast cancer cell lines, high-metastatic cell lines and breast cancer tissues than in chemosensitive cell lines, low-metastatic cell lines, and breast cancer tissues. Overexpression of CXCR2 promoted cell proliferation, migration, invasion, cell anti-apoptosis, tumor formation, metastasis, and chemoresistance, but silencing of CXCR2 inhibited those activities both in vitro and in vivo. Mechanism studies revealed that CXCR2 suppresses AKT1 to promote breast cancer metastasis and chemoresistance through cyclooxygenase-2 (COX-2; PTGS2) to regulate caveolin-1, MMP2, MMP9, E-cardherin, and beta-catenin, which can be inversed by knock down of CXCR2 or COX-2, and over expression of AKT1 and P85alpha. Additionally, over expression of CXCR2 and COX-2, or silencing of PI3K/AKT1 inhibits p53 phosphorylation (Serine 15) and E2F1 expression, but activates MDM2, Bcl-xL and Bcl-2, leading to increased anti-apoptosis. Tissue microarray analysis from 300 breast cancer patients also indicated that over expression of CXCR2 is associated with enhanced COX2 expression and reduced AKT1 expression in metastatic and chemoresistant breast carcinomas (P < 0.001), which may be used to predict breast cancer development. Conclusions: Our results suggest that CXCR2 controls breast cancer metastasis and chemoresistance through regulating COX-2 and AKT1. Thus, antagonists of CXCR2 and COX-2 may be used synergistically to treat breast cancer patients particularly with high metastasis and chemoresistance. Citation Format: Han Xu, Fengjuan Lin, Ziliang Wang, Jiao Meng, Huizhen Sun, Zihao Qi, Yan Wang, Zhouluo Ou, Zhimin Shao, Genhong Di, Gong Yang. CXCR2 controls breast cancer metastasis and chemoresistance through PI3K/AKT and COX-2 signalings. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 548. doi:10.1158/1538-7445.AM2013-548 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.