Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells

Oncogene. 2002 Sep 26;21(43):6573-86. doi: 10.1038/sj.onc.1205847.

Abstract

Most breast cancers arise from luminal epithelial cells and 25-30% of these tumours overexpress the ErbB-2 receptor. Herein, a non-transformed, immortalized cell system was used to investigate the effects of ErbB-2 overexpression in luminal epithelial cells. The phenotypic consequence of ErbB-2 overexpression is a shortening of the G1 phase of the cell cycle and early S phase entry, which leads to hyperproliferation. We show that this effect was mediated through the up-regulation of cdk6 and cyclins D1 and E, and enhanced degradation and relocalization of p27(Kip1). These changes were effected predominantly through enhanced MAPK signalling, resulting in cdk2 hyperactivation. PI3K signalling also participated in cell cycle progression, since PI3K and MAPK coordinately regulated changes in cyclin D1 and cdk6 expression. Cdk4 activity was not required for cell cycle progression in these cells, and was constitutively inhibited through its association with p16(INK4A). MAPK-dependent induction of p21(Cip1) was also necessary for G1 phase progression, although its degradation by the proteasome was required for S phase entry. These data provide new insights into the complex molecular mechanisms underlying mitogenic cell cycle control in luminal epithelial cells, the cell type relevant to primary breast cancer, and show how ErbB-2 overexpression subverts this normal control.

MeSH terms

  • Breast / cytology*
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / pathology
  • CDC2-CDC28 Kinases*
  • Cell Cycle
  • Cell Division
  • Cell Transformation, Neoplastic
  • Cyclin D1 / biosynthesis
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / biosynthesis
  • Cyclins / analysis
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells
  • Female
  • Humans
  • Microfilament Proteins / physiology
  • Mitogen-Activated Protein Kinases / physiology
  • Muscle Proteins*
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Proto-Oncogene Proteins c-myc / physiology
  • Receptor, ErbB-2 / physiology*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Microfilament Proteins
  • Muscle Proteins
  • Proto-Oncogene Proteins c-myc
  • Tagln protein, mouse
  • Cyclin D1
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinases