Abstract 693: Evaluating the role of CXCR2 receptor and its ligand in breast cancer therapy resistance

Abstract

Abstract Breast cancer is the second leading cause of cancer deaths among women after lung cancer, accounting for more than 40,000 deaths each year. Although there has been advancement in the treatment and diagnosis of breast cancer, therapy resistance and relapse are still big hurdles in the way. Recent reports and our preliminary studies suggest that malignant cells that survive the initial chemo- and radiation therapy express higher levels of CXCR2 ligands which might provide a survival benefit to malignant tumors leading to therapy resistance. The specific objective for this study involves targeting CXCR2 receptor and its ligands mediated signaling for therapy resistance in mammary tumor cells. Our hypothesis is that CXCR2 along with its ligands plays an important role in therapy resistance and that targeting this signaling pathway will provide an effective strategy to overcome the problem. We used mammary tumor cells expressing different levels of CXCR2 (Cl66-wt and Cl66-shCXCR2) and examined their response to Paclitaxel and Doxorubicin. We observed significant enhancement of paclitaxel and doxorubicin-mediated toxicity at lower concentrations in Cl66-shCXCR2 cells as compared to Cl66-wt cells. Moreover, we observed an increase in the expression of CXCL1, a CXCR2 ligand, with increasing doses of drugs. However, paclitaxel and doxorubicin induced CXCL-1 levels was significantly lower in Cl66-shCXCR2 cells as compared to Cl66-wt cells. To further validate our findings we selected Cl66 against paclitaxel and doxorubicin resistant cells by treating with increasing doses of these drugs. Cells were maintained in 500nM doxorubicin and 400nM paclitaxel. We analyzed the sensitivity of these cells to doxorubicin and paclitaxel in comparison to wild type parent cells. We observed that resistant cells survive even at higher concentrations (higher than at which they are maintained) of drugs. Although, paclitaxel resistant cells appears to be sensitive at higher doses of paclitaxel when compared to doxorubicin resistant cells in the same set of experiments. Further studies showed an increase in the expression of CXCL1 in the supernatant of these cells after drug treatment. The expression of CXCL1 was higher even at the basal level in the resistant cells in comparison to the parent cells. As it has been shown that expression of CXCR2 ligands increase after chemotherapy, we examined the expression profile of various CXCR2 ligands in these cells at the mRNA level. We observed that these cells express higher levels of CXCL5, CXCL3 and CXCL7, in comparison to parent Cl66 cells. Together, these results demonstrate that i) CXCR2 and its ligand-mediated signaling plays an important role in the drug resistance of mammary tumors cells; ii) that paclitaxel seems to be more effective against mammary tumor cells in comparison to doxorubicin; and iii) targeting CXCR2 expression enhanced chemotherapeutic responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2011-693