CD146 expression in human breast cancer cell lines induces phenotypic and functional changes observed in Epithelial to Mesenchymal Transition

PLoS One. 2012;7(8):e43752. doi: 10.1371/journal.pone.0043752. Epub 2012 Aug 30.

Abstract

Background: Metastasis is an important step in tumor progression leading to a disseminated and often incurable disease. First steps of metastasis include down-regulation of cell adhesion molecules, alteration of cell polarity and reorganization of cytoskeleton, modifications associated with enhanced migratory properties and resistance of tumor cells to anoikis. Such modifications resemble Epithelial to Mesenchymal Transition (EMT). In breast cancer CD146 expression is associated with poor prognosis and enhanced motility.

Methodology/principal findings: On 4 different human breast cancer cell lines, we modified CD146 expression either with shRNA technology in CD146 positive cells or with stable transfection of CD146 in negative cells. Modifications in morphology, growth and migration were evaluated. Using Q-RT-PCR, we analyzed the expression of different EMT markers. We demonstrate that high levels of CD146 are associated with loss of cell-cell contacts, expression of EMT markers, increased cell motility and increased resistance to doxorubicin or docetaxel. Experimental modulation of CD146 expression induces changes consistent with the above described characteristics: morphology, motility, growth in anchorage independent conditions and Slug mRNA variations are strictly correlated with CD146 expression. These changes are associated with modifications of ER (estrogen receptor) and Erb receptors and are enhanced by simultaneous and opposite modulation of JAM-A, or exposure to heregulin, an erb-B4 ligand.

Conclusions: CD146 expression is associated with an EMT phenotype. Several molecules are affected by CD146 expression: direct or indirect signaling contributes to EMT by increasing Slug expression. CD146 may also interact with Erb signaling by modifying cell surface expression of ErbB3 and ErbB4 and increased resistance to chemotherapy. Antagonistic effects of JAM-A, a tight junction-associated protein, on CD146 promigratory effects underline the complexity of the adhesion molecules network in tumor cell migration and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / pathology*
  • CD146 Antigen / genetics*
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Epithelial-Mesenchymal Transition* / drug effects
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Neuregulin-1 / pharmacology
  • Phenotype*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / metabolism
  • Receptors, Estrogen / metabolism

Substances

  • CD146 Antigen
  • Cell Adhesion Molecules
  • F11R protein, human
  • Neuregulin-1
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Estrogen

Grant support

This work was supported in part by Institut Paoli-Calmettes, and by an “Institut National du Cancer” (INCa) “Appel à Projets Libres 2007” to Christian Chabannon. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.