Abstract LB-260: CCR5 antagonists block basal breast cancer and prostate cancer metastasis in vivo.

Abstract

Abstract The identification of new therapeutic targets and treatments to reduce tumor metastasis homing requires alternative interrogation approaches. Interrogation of microarray analysis of 2,254 human breast cancers demonstrated increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes of breast cancer. Genome wide interrogation of pathways activated in patient normal breast vs. tumor identified upregulation of a CCR5 signaling module. Human breast cancer cell lines expressed CCR5 by flow cytometry, and displayed a functional response to CCL5 by calcium mobilization assays and invasion assays. Using isogenic oncogene transformed breast and prostate cancer cell lines, we show oncogene transformation induces CCR5 expression and that the subpopulation of cells that express functional CCR5 display increased invasiveness. CCR5 promoted metastasis homing in vivo. The CCR5 antagonists Maraviroc and Vicriviroc, developed to block CCR5 HIV co-receptor function, reduced in vitro invasion of basal breast cancer and prostate cancer cell lines without affecting cell proliferation or viability. In a series of preclinical mouse models, Maraviroc decreased breast pulmonary metastasis. The isogenic prostate cancer cell lines metastasized to bones in immune-competent mice representing an ideal model for testing anti-metastasis therapies. Maraviroc and Vicriviroc reduced prostate cancer metastasis to brain, bones and lungs. Our findings provide evidence for a key role of CCL5/CCR5 in the metastasis of basal breast cancer and prostate cancer cell lines, and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype and prostate cancer. Citation Format: Richard G. Pestell. CCR5 antagonists block basal breast cancer and prostate cancer metastasis in vivo. [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 LB-260. doi:10.1158/1538-7445.AM2013-LB-260