Stem Cell and Regenerative Medicine

Statement of the Problem: Both Cancer Stem cell (CSCs) and normal tissue stem cells possess self-renewal capacity in CSCs self-renewal is deregulated. The term stemness is referred to the integrated functioning of molecular programs that govern and maintain the stem cell state. CSC possesses clinically relevant properties as they (1) contribute to metastasis (2) survive many commonly employed cancer therapeutics (3) Express transcriptional signatures that are predictive of poor patient survival. In order to target CSC it is necessary to define tractable molecular genetic drivers.

Findings: Specific genetic drivers of CSC were defined in mice including NFkB, cyclin D1, c-Jun, p21Cip1, Dach1 (retinal determination gene network), nuclear receptor acetylation sites and the G-protein coupled receptor CCR5. CCR5 was induced by a variety of mammary oncogenes and current chemotherapies. Small molecular inhibitors of CCR5 reduced cancer stem cells number. Enhanced cancer cell killing induced by standard chemotherapy and abrogated cancer metastasis in vivo. CCR5 inhibitors were effective independently of the genetic driver of the breast cancer.

Conclusion: Because CCR5 expression is induced in breast cancer cells, but not in normal epithelial cells and CCR5 inhibitors enhanced cell killing of standard therapies, a reduction in chemotherapy dose and thereby reduction in side effects is feasible. CCR5 inhibitors have been extensively studied and proven safe in humans for HIV therapy, therefore repurposing for selective CSC treatment of breast cancer metastasis appears feasible.