Abstract P5-04-04: 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. The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression are controversial. Cancer metastasis is regulated by chemokines in the microenvironment. Chemokines bind to cell surface receptors that belong to the G-protein-coupled receptor family (GPCRs), controlling diverse biological and pathological processes from immune surveillance, inflammation, and cancer. Previous studies of human breast cancer and breast cancer cell lines demonstrated that the chemokine receptors CXCR4 and CCR7 are expressed in breast cancer cells, malignant breast tumors, and metastasis. Their related ligands, CXCL12 (SDF1) and CCL21, are also expressed at the site of metastasis. Subsequent studies identified altered expression of CCL5 (RANTES) in breast cancer patients, correlating with disease progression. CCL5 can be expressed and secreted either by breast cancer cells or by non-malignant stromal cells at the primary or metastatic sites. However, the roles of CCL5 and its receptors in breast cancer are not fully understood. CCL5 facilitates disease progression by recruiting and modulating the activity of inflammatory cells, which subsequently remodel the tumor microenvironment. Accordingly, inhibition of CCR5 by a peptide antagonist reduced leukocyte infiltration and reduced tumor growth after subcutaneous injection of 410.4 mammary carcinoma cells into immunocompetent mice. Our recent 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. Interrogation of pathways activated in patient normal breast vs. tumor identified up regulation of a CCR5 signaling module. At the same time, we also extended our research to prostate cancers. Using isogenic oncogene transformed breast and prostate cancer cell lines we show oncogene transformation induces CCR5 expression in breast and prostate epithelial cells. Further we show that the subpopulation of cells that express functional CCR5 display increased invasiveness. Studies in vivo demonstrated that CCR5 promoted metastasis homing. The FDA approved CCR5 antagonists Maraviroc or 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, used at equivalent doses to those used in treatment of humans for HIV, 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. CCR5 was expressed in the metastasis in the bones. Maraviroc 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 Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-04.