title: ΔNp63α Promotes Breast Cancer Cell Motility through the Selective Activation of Components of the Epithelial-to-Mesenchymal Transition Program.
abstract: Cell identity signals influence the invasive capability of tumor cells, as demonstrated by the selection for programs of epithelial-to-mesenchymal transition (EMT) during malignant progression. Breast cancer cells retain canonical epithelial traits and invade collectively as cohesive groups of cells, but the signaling pathways critical to their invasive capabilities are still incompletely understood. Here we report that the transcription factor ΔNp63α drives the migration of basal-like breast cancer (BLBC) cells by inducing a hybrid mesenchymal/epithelial state. Through a combination of expression analysis and functional testing across multiple BLBC cell populations, we determined that ΔNp63α induces migration by elevating the expression of the EMT program components Slug and Axl. Interestingly, ΔNp63α also increased the expression of miR-205, which can silence ZEB1/2 to prevent the loss of epithelial character caused by EMT induction. In clinical specimens, co-expression of various elements of the ΔNp63α pathway confirmed its implication in motility signaling in BLBC. We observed that activation of the ΔNp63α pathway occurred during the transition from noninvasive ductal carcinoma in situ to invasive breast cancer. Notably, in an orthotopic tumor model, Slug expression was sufficient to induce collective invasion of E-cadherin-expressing BLBC cells. Together, our results illustrate how ΔNp63α can drive breast cancer cell invasion by selectively engaging promigratory components of the EMT program while, in parallel, still promoting the retention of epithelial character.
authors: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Tuyen T
authors: TT
authors: Dang
authors: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Matthew A
authors: MA
authors: Esparza
authors: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Erin A
authors: EA
authors: Maine
authors: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors: Jill M
authors: JM
authors: Westcott
authors: Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, Texas. gray.pearson@utsouthwestern.edu.
authors: Gray W
authors: GW
authors: Pearson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000473:pathology*; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D015820:Cadherins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000094963:Axl Receptor Tyrosine Kinase; C534425:MIR205, human; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C115051:TP63 protein, human