The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells

Oncotarget. 2014 Apr 30;5(8):2065-76. doi: 10.18632/oncotarget.1779.

Abstract

In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / pathology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Fluorescent Antibody Technique
  • Focal Adhesion Kinase 1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Heterografts
  • Humans
  • Immunohistochemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Invasiveness
  • Polycomb Repressive Complex 1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Array Analysis

Substances

  • CKAP4 protein, human
  • Membrane Proteins
  • Polycomb Repressive Complex 1
  • RNF2 protein, human
  • Focal Adhesion Kinase 1
  • PTK2 protein, human