Obesity-Associated Leptin Signaling Promotes Chemotherapy Resistance in Basal-Like Breast Cancer: The Role of Tumor-Associated Macrophages

Abstract

Abstract Objectives Obesity is associated with a reduced response to cytotoxic chemotherapies. Given that the adipokine leptin has been shown to promote macrophage production of pro-tumor cytokines, we hypothesized that leptin-induced pro-tumor macrophage polarization is a key mediator of obesity-associated docetaxel resistance. Methods Wild-type C57BL/6 mice were fed a low-fat control (10% kcal from fat) or high-fat diet-induced obesity (DIO; 60% kcal from fat) diet for 15 weeks, then orthotopically injected with 2 mouse mammary tumor cell lines: EWnt-S (scrambled shRNA) and EWnt-L (shRNA to the leptin receptor) in the 9th and 4th mammary glands, respectively. Mice in each group were then randomized to vehicle or docetaxel (20 mg/kg/week IV for 3 weeks). The transcriptomes of both tumors (n = 6/group) were analyzed by microarray, and cell type enrichment analysis performed using the webtool xCell. The in vitro effects of leptin +/− docetaxel on macrophage polarization as well as cancer cell cytotoxicity and markers of invasive capacity are currently being assessed. Results The DIO mice had greater body weight and % body fat at euthanization versus control mice (P < 0.01 for both). Docetaxel treatment in DIO mice reduced tumor growth rate in EWnt-L tumors (P < 0.05), but not EWnt-S tumors. In contrast, docetaxel treatment reduced the EWnt-L and EWnt-S tumor growth rate in control mice (P < 0.05 for both). xCell analysis indicated that docetaxel treatment increased M2 macrophage levels in the DIO mouse tumors, but not the controls. Leptin receptor knockdown attenuated this effect. In addition, key genes related to “macrophage markers”, “cytokines and inflammatory response”, and “interleukin (IL)-6 signaling” were differentially expressed in docetaxel-treated EWnt-S tumors from DIO versus control mice. Conclusions These results indicate that leptin signaling mediates obesity-induced docetaxel resistance in the E-Wnt model of basal-like breast cancer. They also suggest that docetaxel interacts with leptin signaling to promote an increase in tumor-promoting M2 macrophages and subsequent docetaxel resistance. This hypothesis is currently being explored through our in vitro studies. Funding Sources This work was supported by a grant from the Developmental Funding Program, Lineberger Comprehensive Cancer Center, UNC Chapel Hill.