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This abstract was not presented at the conference. Citation Format: Zhao Y, Sun H, Jin W. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-08-08.

This abstract was not presented at the symposium.

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.

Abstract Background and Purpose-Ovarian cancer is the most lethal gynecological malignancy in women, but the essential mechanism remains unclear. Studies have shown that many ribosomal proteins are dysfunctional in various tumors. The small ribosomal protein subunit S7 (RPS7) has been reported to interact with MDM2 and may function as a tumor suppressor, but its role in cancer development is largely unknown. Here, we examined the molecular function of RPS7 in human ovarian cancer. Experimental Design-Retrovirus-mediated small hairpin RNA (shRNA) was used to silence the expression of RPS7 in ovarian cancer cell lines SKOV3 and OVCA433, named SKOV3-RPS7i, OVCA433-RPS7i plus their GFP shRNA (GFPi) controls. Cell proliferation, cell cycle, apoptosis, cell migration and invasion, and tumor growth were tested to determine the function of RPS7 in ovarian cancer. Results-Immunostaining of RPS7 showed that RPS7 was higher in ovarian cancer tissues than in nomal tissues. Silencing of RPS7 in SKOV3 and OVCA433 cells promoted cell growth and markedly enhanced anchorage-independent colony formation. Depletion of RPS7 accelerated cell cycle progression through G1-S transition, which was evidenced by alterations of cell cycle regulatory proteins including p21waf1/cip1, CDK2/4, Cyclin B1, and Cyclin D1. Knockdown of RPS7 weakened cell apoptosis by increasing the expression of anti-apoptotic proteins including BCL2 and BCL-XL, and decreasing the expression of apoptotic molecules including p27cip/kip, BAK, and BAD. However, knockdown of RPS7 reduced cell migration and invasion. Further analysis showed that the expression of β-catenin, MMP2, and MMP13 was decreased, but E-cadherin was increased in RPS7-silenced cells compared with in controls, indicating that RPS7 is associated with metastasis. Moreover, P85α, P110α and AKT1/2 were decreased in SKOV3-RPS7i and OVCA433-RPS7i, suggesting that RPS7 functions through PI3K/AKT signal pathway. Although the basal levels of ERK 1/2, MEK1/2, and p38 were inconsistently altered, but the phosphorylation of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), and p38 (Thr180/Tyr182) was reduced in SKOV3-RPS7i and OVCA433-RPS7i cells, compared with in controls. Thus, our results suggested that RPS7 appears to regulate cell proliferation, apoptosis, and tumorigenesis through PI3K/AKT and MAPK signal pathways. Conclusion-RPS7 may function as an anti-tumor factor in ovarian tumorigenesis through PI3K/AKT and MAPK signal pathways. Citation Format: Ziliang Wang, Lili Lu, Jianmin Sun, Jiao Meng, Wen Gao, Yan Wang, Huizhen Sun, Jin Hou, Hongyu Gu, Zhen Wang, Yuhu Xin, Gong Yang. The Small Ribosomal Protein Subunit S7 Functions as a Tumor Suppressor to regulate ovarian tumorigenesis through PI3K/AKT and MAPK pathways. [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 4303. doi:10.1158/1538-7445.AM2013-4303