CCR5 antagonist blocks metastasis of basal breast cancer cells.
The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells 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.
Kimmel Cancer Center, Department of Cancer Biology and Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA. marcovelasco@unam.mx
Marco
M
Velasco-Velázquez
Xuanmao
X
Jiao
Marisol
M
De La Fuente
Timothy G
TG
Pestell
Adam
A
Ertel
Michael P
MP
Lisanti
Richard G
RG
Pestell
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5 / Q000502:physiology; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077592:Maraviroc; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D003510:Cyclohexanes; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc; C486781:vicriviroc