Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

Cancer Res. 2009 May 15;69(10):4545-52. doi: 10.1158/0008-5472.CAN-08-1694. Epub 2009 May 5.

Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a dual-function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two nonmalignant human mammary epithelial cell lines that form polarized, growth-arrested structures (acini) when cultured in three-dimensional laminin-rich extracellular matrix gels (lrECM). As acini begin to form, PTEN accumulates both in the cytoplasm and at cell-cell contacts where it colocalizes with the E-cadherin/beta-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in Skbr-3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in three-dimensional lrECM, indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus seems to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast / cytology
  • Breast / physiology*
  • Cadherins / physiology*
  • Cell Culture Techniques
  • Cell Division / physiology
  • Culture Media
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression Profiling
  • Genes, Reporter
  • Humans
  • Morphogenesis
  • Oligonucleotide Array Sequence Analysis
  • PTEN Phosphohydrolase / physiology*
  • RNA, Messenger / genetics
  • Signal Transduction / physiology*

Substances

  • Cadherins
  • Culture Media
  • RNA, Messenger
  • PTEN Phosphohydrolase