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

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. Int. J. Cancer 86:644–651, 2000. © 2000 Wiley‐Liss, Inc.