ΔNP63α Transcriptionally Activates Chemokine Receptor 4 (CXCR4) Expression to Regulate Breast Cancer Stem Cell Activity and Chemotaxis

Delta NP63 alpha, the predominant TP63 isoform expressed in diverse epithelial tissues, including the mammary gland, is required for the preservation of stem cells and has been implicated in tumorigenesis and metastasis. Despite data characterizing Delta NP63 alpha as a master regulator of stem cell activity, identification of the targets underlying these effects is incompletely understood. Recently, Delta NP63 alpha was identified as a key regulator in the promotion of proinflammatory programs in squamous cell carcinoma of the head and neck. Inflammation has been implicated as a potent driver of cancer stem cell phenotypes and metastasis. In this study, we sought to identify novel targets of Delta NP63 alpha that confer cancer stem cell and prometastatic properties. Data presented here identify the gene encoding the chemokine receptor 4 (CXCR4) as a transcriptional target of Delta NP63 alpha. Our data indicate that Delta NP63 alpha enhances CXCR4 expression in breast cancer cells via its binding at two regions within the CXCR4 promoter. The CXCR4 antagonist AMD3100 was used to demonstrate that the pro-stem cell activity of Delta NP63 alpha is mediated through its regulation of CXCR4. Importantly, we show that Delta NP63 alpha promotes the chemotaxis of breast cancer cells towards the CXCR4 ligand SDF1 alpha, a process implicated in the trafficking of breast cancer cells to sites of metastasis. This study highlights CXCR4 as a previously unidentified target of Delta NP63 alpha, which plays a significant role in mediating Delta NP63 alpha-dependent stem cell activity and chemotaxis toward SDF1 alpha. Our findings suggest that Delta NP63 alpha regulation of CXCR4 may have strong implications in the regulation of cancer stem cells and metastasis. (C) 2014 AACR.