Abstract LB-45: VEGFR3 signaling facilitates mammary tumor cells to resist chemotherapy

Abstract

Abstract Breast cancer is a deadly disease which accounts for more than 40,000 deaths each year in United States. With the availability of various treatment options, side effects and resistance associated with them is also becoming a major concern for the treatment of breast cancer. How breast cancer cells evade chemotherapy still remains a vast area for research. In this study, we proposed that mammary tumor cells resist cell death via VEGFR3 signaling pathway. To test our hypothesis, we used doxorubicin and paclitaxel resistant murine mammary tumor cells (Cl66-Dox and Cl66-Pac) which have been developed in our laboratory. When implanted in female Balb/c mice they form more aggressive tumor than the parent cells (Cl66) from which they have been derived. We observed that these resistant cells have higher expression of VEGFR3 receptor than parent cells at mRNA level. Treatment with VEGFR3 kinase inhibitor, MAZ51, Cl-66Dox and Cl66-Pac cells showed 50% growth inhibition at 10uM dose, suggesting VEGFR3 receptor activation as one of the mechanism for resistance. Moreover, when implanted in mice, tumor formed by resistant cells responded well to MAZ51 treatment with slower tumor growth in comparison to control group consistent with our in vitro data. However, when we treated mice bearing resistant tumors first with chemotherapeutic drug, docetaxel followed by MAZ51, we observed a significant decrease in tumor growth and tumor weight, examined upon endpoint analysis. These results suggest that combination treatment is more effective in inhibiting drug-resistant tumors growth in comparison to drug and inhibitor alone as determined by reduced tumor volume and weight in combination treatment group. Overall, our in vivo data showed that blocking VEGFR3 signaling pathway makes drug-resistant mammary tumor cells susceptible to chemotherapy suggesting the use of inhibitors for this signaling pathway to be beneficial for drug-resistant mammary tumors. Citation Format: Bhawna Sharma, Michelle L. Varney, Rakesh K. Singh. VEGFR3 signaling facilitates mammary tumor cells to resist chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-45. doi:10.1158/1538-7445.AM2014-LB-45