title: MUC1-C Represses the Crumbs Complex Polarity Factor CRB3 and Downregulates the Hippo Pathway.
abstract: Apical-basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C--terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known whether MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer (TNBC) cells. MUC1-C associates with ZEB1 on the CRB3 promoter and represses CRB3 transcription. Notably, CRB3 activates the core kinase cassette of the Hippo pathway, which includes LATS1 and LATS2. In this context, targeting MUC1-C was associated with increased phosphorylation of LATS1, consistent with activation of the Hippo pathway, which is critical for regulating cell contact, tissue repair, proliferation, and apoptosis. Also shown is that MUC1-C--mediated suppression of CRB3 and the Hippo pathway is associated with dephosphorylation and activation of the oncogenic YAP protein. In turn, MUC1-C interacts with YAP, promotes formation of YAP/β-catenin complexes, and induces the WNT target gene MYC. These data support a previously unrecognized pathway in which targeting MUC1-C in TNBC cells (i) induces CRB3 expression, (ii) activates the CRB3-driven Hippo pathway, (iii) inactivates YAP, and thereby (iv) suppresses YAP/β-catenin-mediated induction of MYC expression.
  
  
  
  These findings demonstrate a previously unrecognized role for the MUC1-C oncoprotein in the regulation of polarity and the Hippo pathway in breast cancer. Mol Cancer Res; 14(12); 1266-76. ©2016 AACR.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Audrey
authors.initials: A
authors.lastname: Bouillez
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ashujit
authors.initials: A
authors.lastname: Tagde
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rehan
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. donald_kufe@dfci.harvard.edu.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D016764:Cell Polarity; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D061986:MCF-7 Cells; D008562:Membrane Glycoproteins / Q000235:genetics*; D018396:Mucin-1 / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C472002:CRB3 protein, human; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases