title: ΔNp63 activates EGFR signaling to induce loss of adhesion in triple-negative basal-like breast cancer cells.
abstract: OBJECTIVE
  The basal-A subtype of triple-negative breast cancer is characterized by high levels of ΔNp63. Various functions have been proposed for p63 in breast cancer initiation and growth, and p63 mediates chemotherapeutic response in a subset of triple-negative breast cancers. We investigated the signaling pathways that are controlled by ΔNp63 in basal-A triple-negative breast cancer.
  
  
  METHODS
  Human basal-A triple-negative breast cancer cell lines with ΔNp63α induction or inhibition were studied, along with primary human triple-negative breast cancer tissues. Proteomic, phospho-kinase array, mRNA measurements, and immunohistochemistry were employed.
  
  
  RESULTS
  Global phosphoproteomics identified increased EGFR phosphorylation in MDA-MB-468 cells expressing ΔNp63α. ΔNp63α expression increased EGFR mRNA, total EGFR protein, and phospho-EGFR(Y1086), whereas silencing endogenous ΔNp63 in HCC1806 cells reduced both total and phospho-EGFR levels and inhibited the ability of EGF to activate EGFR. EGFR pathway gene expression analysis indicated that ΔNp63 alters EGFR-regulated genes involved in cell adhesion, migration, and angiogenesis. Addition of EGF or neutralizing EGFR antibodies demonstrated that EGFR activation is responsible for ΔNp63-mediated loss of cellular adhesion. Finally, immunohistochemical staining showed that p63-positive triple-negative breast cancers were more likely to express high levels of EGFR than p63-negative cancers, corroborated by in silico analysis of gene expression profiling data.
  
  
  CONCLUSIONS
  These data identify EGFR as a major target for ΔNp63 regulation that influences cancer cell adhesion in basal-like triple-negative breast cancer.
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Holcakova
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Marta
authors.initials: M
authors.lastname: Nekulova
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Paulina
authors.initials: P
authors.lastname: Orzol
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Nenutil
authors.affiliation: Clinic of Comprehensive Cancer Care, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Podhorec
authors.affiliation: Clinic of Comprehensive Cancer Care, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Svoboda
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Dvorakova
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Mariana
authors.initials: M
authors.lastname: Pjechova
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Hernychova
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic. vojtesek@mou.cz.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
authors.affiliation: RECAMO, Masaryk Memorial Cancer Centre, Zluty kopec 7, 65633, Brno, Czech Republic. philip.coates@mou.cz.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Coates
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D040901:Proteomics; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Adhesion; Breast cancer; EGFR; Invasion; Metastasis; p63