Tissue Engineering and Regenerative Medicine

Tumor initiating cells convey stem-like features and contribute to therapeutic resistance and tumor metastases. Cancer stem cells are protected against chemotherapy- and radiotherapy- induced death, through mechanisms that protect genomic integrity via induction of DNA damage sensing and DNA repair machinery. In mammalian cells, double-stranded breaks (DSB) may be repaired by either homology directed recombination (HDR), or non-homologous end joining (NHEJ) and single-strand annealing (SSA). Defects in these repair mechanisms can result in chromosomal fusions, translocations and breaks. The molecular mechanisms linking cancer stem cells and DNA repair are poorly understood. Herein, the chemokine receptor CCR5, which is known to contribute to breast cancer progression and metastasis, was shown to promote stem cell like properties and enhance DNA repair. Reintroduction of CCR5 into CCR5-negative cells promoted breast tumor stem cell expansion, metastases, and the induction of DNA repair gene expression. CCR5 was shown to enhance the repair of DSBs by inducing HDR and SSA-based DNA repair. The finding that CCR5 on cancer cells augments DNA repair and cancer stem cell expansion suggests CCR5 inhibitors may enhance the tumor specific activities of DDR-based treatments. (Up to 250 words)