NEDD9 Is a Positive Regulator of Epithelial-Mesenchymal Transition and Promotes Invasion in Aggressive Breast Cancer

PLoS One. 2011;6(7):e22666. doi: 10.1371/journal.pone.0022666. Epub 2011 Jul 28.

Abstract

Epithelial to mesenchymal transition (EMT) plays an important role in many biological processes. The latest studies revealed that aggressive breast cancer, especially the triple-negative breast cancer (TNBC) subtype was frequently associated with apparent EMT, but the mechanisms are still unclear. NEDD9/HEF1/Cas-L is a member of the Cas protein family and was identified as a metastasis marker in multiple cancer types. In this study, we wished to discern the role of NEDD9 in breast cancer progression and to investigate the molecular mechanism by which NEDD9 regulates EMT and promotes invasion in triple-negative breast cancer. We showed that expression of NEDD9 was frequently upregulated in TNBC cell lines, and in aggressive breast tumors, especially in TNBC subtype. Knockdown of endogenous NEDD9 reduced the migration, invasion and proliferation of TNBC cells. Moreover, ectopic overexpression of NEDD9 in mammary epithelial cells led to a string of events including the trigger of EMT, activation of ERK signaling, increase of several EMT-inducing transcription factors and promotion of their interactions with the E-cadherin promoter. Data presented in this report contribute to the understanding of the mechanisms by which NEDD9 promotes EMT, and provide useful clues to the evaluation of the potential of NEDD9 as a responsive molecular target for TNBC chemotherapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Blotting, Western
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Movement
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Colony-Forming Units Assay
  • Epithelial-Mesenchymal Transition*
  • Female
  • Humans
  • Luciferases / metabolism
  • MAP Kinase Signaling System
  • Neoplasm Invasiveness
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Wound Healing

Substances

  • Adaptor Proteins, Signal Transducing
  • Cadherins
  • NEDD9 protein, human
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Snail Family Transcription Factors
  • Transcription Factors
  • Luciferases
  • Receptor, ErbB-2