The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5 breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response-based treatments, allowing a dose reduction of standard chemotherapy and radiation. This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. .
Src family kinases (SFKs) integrate signal transduction for multiple receptors, regulating cellular proliferation invasion and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. In order to determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cells (PEC) lines were grown in vivo vs. tissue cultures. The whole body, bone and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors.
<p>Supplemental figure 1-11 which include: (1) High resolution image of figure 1A. (2) Supplemental data for the relation between CCR5+ cells and breast cancer stem cells. (3) In vivo tumor formation of CCR5+ vs CCR5- cells. (4) In vivo tumor formation of CCR5 overexpression cells vs vector control cells. (5) Gene expression profile of CCR5+ vs CCR5- cells. (6) The effects of CCR5 on DNA damage repair in MDA-MB-231 cells. (7) A schematic representation of the DNA damage signaling pathways, with target genes enriched in CCR5+ cells. (8) The effects of CCR5 on DNA damage repair based on DNA damage repair reporter assays. (9) The functional synergy of cell killing between CCR5 inhibitors and Doxorubicin. (10) Single cell RNAseq of CCR5+ vs. CCR5- SUM-159 cells. (11) Enrichment of CCR5+ cells in doxorubicin resistant cells.</p>
<p>Supplemental figure 1-11 which include: (1) High resolution image of figure 1A. (2) Supplemental data for the relation between CCR5+ cells and breast cancer stem cells. (3) In vivo tumor formation of CCR5+ vs CCR5- cells. (4) In vivo tumor formation of CCR5 overexpression cells vs vector control cells. (5) Gene expression profile of CCR5+ vs CCR5- cells. (6) The effects of CCR5 on DNA damage repair in MDA-MB-231 cells. (7) A schematic representation of the DNA damage signaling pathways, with target genes enriched in CCR5+ cells. (8) The effects of CCR5 on DNA damage repair based on DNA damage repair reporter assays. (9) The functional synergy of cell killing between CCR5 inhibitors and Doxorubicin. (10) Single cell RNAseq of CCR5+ vs. CCR5- SUM-159 cells. (11) Enrichment of CCR5+ cells in doxorubicin resistant cells.</p>
<p>The figure legends of Supplemental figure 1-11 which include: (1) High resolution image of figure 1A. (2) Supplemental data for the relation between CCR5+ cells and breast cancer stem cells. (3) In vivo tumor formation of CCR5+ vs CCR5- cells. (4) In vivo tumor formation of CCR5 overexpression cells vs vector control cells. (5) Gene expression profile of CCR5+ vs CCR5- cells. (6) The effects of CCR5 on DNA damage repair in MDA-MB-231 cells. (7) A schematic representation of the DNA damage signaling pathways, with target genes enriched in CCR5+ cells. (8) The effects of CCR5 on DNA damage repair based on DNA damage repair reporter assays. (9) The functional synergy of cell killing between CCR5 inhibitors and Doxorubicin. (10) Single cell RNAseq of CCR5+ vs. CCR5- SUM-159 cells. (11) Enrichment of CCR5+ cells in doxorubicin resistant cells.</p>
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