Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.

Regional Centre of Applied and Molecular Oncology Masaryk Memorial Cancer Institute Zluty kopec 7 656 53 Brno Czech Republic

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Tumour Biol. 2016 Jun;37(6):8469. doi: 10.1007/s13277-016-5055-5. PubMed

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Histopathology. 2007 Mar;50(4):434-8 PubMed

Breast Cancer Res Treat. 2014 Jun;145(2):339-48 PubMed

J Clin Invest. 2011 Jul;121(7):2750-67 PubMed

Mol Cell. 2006 Nov 17;24(4):593-602 PubMed

Nature. 1999 Apr 22;398(6729):708-13 PubMed

Cancer Res. 2011 Mar 1;71(5):1933-44 PubMed

Virchows Arch. 2005 Oct;447(4):688-94 PubMed

J Pathol. 2014 Jan;232(2):142-50 PubMed

Nat Cell Biol. 2014 Oct;16(10):1004-15, 1-13 PubMed

Cancer Cell. 2005 Apr;7(4):363-73 PubMed

J Pathol. 2002 Dec;198(4):417-27 PubMed

Mod Pathol. 2011 Feb;24(2):157-67 PubMed

Cell. 2007 May 4;129(3):523-36 PubMed

PLoS Genet. 2009 Oct;5(10 ):e1000680 PubMed

Virchows Arch. 2013 Sep;463(3):415-25 PubMed

Cancer Res. 2015 Sep 15;75(18):3925-35 PubMed

Annu Rev Pathol. 2010;5:349-71 PubMed

Nature. 1999 Apr 22;398(6729):714-8 PubMed

Cell Death Differ. 2013 Dec;20(12):1698-708 PubMed

Mol Cell. 1998 Sep;2(3):305-16 PubMed

Dev Cell. 2002 May;2(5):607-16 PubMed

Nat Cell Biol. 2006 Jun;8(6):551-61 PubMed

J Clin Pathol. 2010 Aug;63(8):744-7 PubMed

Cell Mol Biol Lett. 2011 Jun;16(2):296-327 PubMed

J Biol Chem. 2013 Feb 1;288(5):3275-88 PubMed

Nat Methods. 2014 Aug;11(8):783-784 PubMed

Cancer Cell. 2006 Dec;10(6):515-27 PubMed

Cell Death Differ. 2010 Oct;17(10):1600-12 PubMed

PLoS One. 2009 May 20;4(5):e5623 PubMed

Nat Struct Mol Biol. 2011 Jul 03;18(8):867-74 PubMed

Cancer Res. 2006 Aug 1;66(15):7589-97 PubMed

Clin Cancer Res. 2013 Dec 1;19(23):6380-8 PubMed

Science. 2013 Mar 29;339(6127):1567-70 PubMed

Cancer Res. 2013 Jan 15;73(2):1020-30 PubMed

Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3499-504 PubMed

Cancer Res. 2003 May 15;63(10):2351-7 PubMed

Cell Cycle. 2007 Feb 1;6(3):255-61 PubMed

Am J Surg Pathol. 2001 Aug;25(8):1054-60 PubMed

Stem Cells. 2008 May;26(5):1253-64 PubMed

J Pathol. 2007 Dec;213(4):384-91 PubMed

Cancer Lett. 2008 May 8;263(1):26-34 PubMed

Histol Histopathol. 2015 May;30(5):503-21 PubMed

J Pathol. 2009 Aug;218(4):428-36 PubMed

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