ΔNP63α transcriptionally activates chemokine receptor 4 (CXCR4) expression to regulate breast cancer stem cell activity and chemotaxis.
ΔNP63α, 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 ΔNP63α as a master regulator of stem cell activity, identification of the targets underlying these effects is incompletely understood. Recently, ΔNP63α 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 ΔNP63α 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 ΔNP63α. Our data indicate that ΔNP63α 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 ΔNP63α is mediated through its regulation of CXCR4. Importantly, we show that ΔNP63α promotes the chemotaxis of breast cancer cells towards the CXCR4 ligand SDF1α, a process implicated in the trafficking of breast cancer cells to sites of metastasis. This study highlights CXCR4 as a previously unidentified target of ΔNP63α, which plays a significant role in mediating ΔNP63α-dependent stem cell activity and chemotaxis toward SDF1α. Our findings suggest that ΔNP63α regulation of CXCR4 may have strong implications in the regulation of cancer stem cells and metastasis.
Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Program in Experimental and Molecular Medicine, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
Andrew J
AJ
DeCastro
Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
Pratima
P
Cherukuri
Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Program in Experimental and Molecular Medicine, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
Amanda
A
Balboni
Department of Pharmacology and Toxicology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. James.DiRenzo@Dartmouth.edu.
James
J
DiRenzo
D001596:Benzylamines; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002633:Chemotaxis; D000080027:Cyclams; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D020033:Protein Isoforms; D019718:Receptors, CXCR4; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C088327:plerixafor