Abstract 3592: Macrophages confer resistance to cisplatin in MTLn3 and MDA-MB 231 breast cancer cells

Abstract

Abstract Drug resistance presents a clinical challenge to the treatment of breast cancer. Stromal cells such as macrophages may play a role in drug resistance. The purpose of this study is to examine the interaction between breast cancer cells and macrophages and its effects on drug therapy resistance. The five-year survival for localized hormone sensitive disease is 98% and as low as 15% for triple negative (ER/PR/Her2) and metastatic disease. Most targeted anticancer therapies, as well as cytotoxic therapies, are burdened by the development of cancer cell resistance. It is hypothesized that the tumor microenvironment may confer innate resistance to drug therapy. It is well established that chemotactic factors found in the tumor microenvironment can promote motility and invasion. We hypothesize that tumor associated macrophages can confer drug resistance to breast cancer cells via overexpression of epidermal growth factor (EGF). EGF is overexpressed in many tumor types and is clinically correlated with a poor overall prognosis. Previous studies have shown that EGF is produced by non-tumor cells in the microenvironment; in particular tumor-associated macrophages (TAM) and endothelial cells. We have previously shown that macrophages and tumor cells, via a paracrine loop, are necessary and sufficient for comigration and invasion. Breast cancer cells produce colony stimulating factor 1 (CSF-1) which positively feeds back to increase macrophage expression of EGF. Increased EGF expression in turn leads to tumor growth and invasion. We selected two triple negative breast cancer cell lines, MDA-MB 231 (human mammary adenocarcinoma) and MTLn3 (rat mammary adenocarcinoma) that were transfected to express GFP. Co-culture cell survival assays were performed with macrophages, fibroblasts, and endothelial cells. All tissue culture was completed in DMEM (HyClone) plus 10% FBS. Cells were grown for 24 hours in co-culture, treated with chemotherapy (doxorubicin or cisplatin at a range of concentrations) for 24 hours, and then analyzed at 72 hours using the DXP-10 Calibur analyzer. Prior to analysis, cells were again replated to measure “replating efficiency” i.e. chemoresistant cell survival. We found that coculture with macrophages increased tumor cell survival upon exposure to cisplatin. We conclude that macrophages are an important component of the tumor microenvironment that may play a role in chemotherapy resistance. Citation Format: Joshua K. Sabari, Ramon Cabrera, Jeffrey Segall. Macrophages confer resistance to cisplatin in MTLn3 and MDA-MB 231 breast cancer cells. [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 3592. doi:10.1158/1538-7445.AM2014-3592