ERbB-2 expression is rate-limiting for epidermal growth factor-mediated stimulation of ovarian cancer cell proliferation

Int J Cancer. 2000 Jun 1;86(5):644-51. doi: 10.1002/(sici)1097-0215(20000601)86:5<644::aid-ijc7>3.0.co;2-t.

Abstract

Over-expression of the ErbB-2 proto-oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. The ErbB-2 receptor is a member of the ErbB family of growth factor receptors, and within this complex signaling network, ErbB-2-containing heterodimers are preferentially formed. To assess whether ErbB-2 is a critical component in epidermal growth factor (EGF)-mediated stimulation of tumor cell proliferation, we used as a model SK-OV-3 ovarian cancer cells, which over-express EGF receptor (EGFR) and ErbB-2 receptors. In these cells, we reduced ErbB-2 mRNA and protein expression by transfection with ErbB-2-targeted hammerhead ribozymes and generated cell lines expressing different levels of ErbB-2. In SK-OV-3 cells, ErbB-2 expression conferred a growth advantage and soft agar experiments revealed that ErbB-2 was rate-limiting for anchorage-independent growth. The induction of colony formation by EGF was completely abrogated in ErbB-2-depleted cells, despite unchanged expression levels and tyrosine phosphorylation of the EGFR. The duration of EGF-mediated c-Fos mRNA up-regulation was decreased in parallel with loss of ErbB-2 expression. Furthermore, the rate of spontaneous apoptosis was increased in ErbB-2-depleted cells. Our results demonstrate that in human ovarian cancer cells the EGFR-ErbB-2 heterodimer, and not the EGFR homodimer, can be rate-limiting for EGF-mediated proliferation, thus suggesting that the oncogenic activity of ErbB-2 in human tumors is due in part to its ability to increase the growth response to stroma-derived EGF-like growth factors.

Publication types

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

MeSH terms

  • Apoptosis
  • Cell Division / drug effects
  • Epidermal Growth Factor / physiology*
  • ErbB Receptors / biosynthesis
  • Female
  • Glycoproteins / physiology
  • Humans
  • Neuregulin-1
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Catalytic / pharmacology
  • Receptor, ErbB-2 / biosynthesis*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / physiology
  • Tumor Cells, Cultured

Substances

  • Glycoproteins
  • Neuregulin-1
  • Proto-Oncogene Proteins c-fos
  • RNA, Catalytic
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2