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A bstract   Cancer stem‐like cells (SLC) resist conventional therapies, necessitating searches for SLC‐specific targets. We established that cyclo‐oxygenase(COX)‐2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E‐2 receptor EP4. Present study revealed that COX‐2 induces SLCs by EP4‐mediated NOTCH/WNT signaling. Ectopic COX‐2 over‐expression in MCF‐7 and SKBR‐3 cell lines resulted in: increased migration/invasion/proliferation, epithelial‐mesenchymal transition (EMT), elevated SLCs (spheroid formation), increased ALDH activity and colocalization of COX‐2 and SLC markers (ALDH1A, CD44, β‐Catenin, NANOG, OCT3/4, SOX‐2) in spheroids. These changes were reversed with COX‐2‐inhibitor or EP4‐antagonist (EP4A), indicating dependence on COX‐2/EP4 activities. COX‐2 over‐expression or EP4‐agonist treatments of COX‐2‐low cells caused up‐regulation of  NOTCH/WNT  genes, blocked with PI3K/AKT inhibitors. NOTCH/WNT inhibitors also blocked COX‐2/EP4 induced SLC induction. Microarray analysis showed up‐regulation of numerous SLC‐regulatory and EMT‐associated genes. MCF‐7‐COX‐2 cells showed increased mammary tumorigenicity and spontaneous multiorgan metastases in NOD/SCID/IL‐2Rγ‐null mice for successive generations with limiting cell inocula. These tumors showed up‐regulation of VEGF‐A/C/D, Vimentin and phospho‐AKT, down‐regulation of E‐Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF‐7‐COX‐2 cells also showed increased lung colonization in NOD/SCID/GUSB‐null mice, an effect reversed with EP4‐knockdown or EP4A treatment of the MCF‐7‐COX‐2 cells.  COX‐2 / EP4 / ALDH1A  mRNA expression in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. In situ immunostaining of human breast tumor tissues revealed co‐localization of SLC markers with COX‐2, supporting COX‐2 inducing SLCs. High  COX‐2 / EP4  mRNA expression was linked with reduced survival. Thus, EP4 represents a novel SLC‐ablative target in human breast cancer. S tem  C ells   2016;34:2290–2305

COX‐2 Induces Breast Cancer Stem Cells via EP4/PI3K/AKT/NOTCH/WNT Axis