The human ErbB receptor family comprises 4 tyrosine kinase receptors (ErbB1 or EGFR, ErbB2, ErbB3, and ErbB4). It is well established that dysregulation of ErbB receptor signaling plays important roles in the progression of various types of cancers, including breast, prostate and colon cancer. Heregulins (also called neuregulins) are a group of EGF-like ligands for the ErbB3 and ErbB4 receptors and are often expressed in breast cancer tissues. In our previous studies, we found that heregulin β1 (HRG) is a potent activator of Rac in breast cancer cells. The Rac activation by HRG is impaired by RNAi depletion of ErbB2 and ErbB3 but not by ErbB4, and it also involves the transactivation of EGFR. In this study, we further determined how Rac activation by HRG mediates breast cancer T-47D cell proliferation. We found that expression of β2-chimaerin, a Rac-GAP, or a dominant negative Rac (N17Rac1) dose-dependently inhibited HRG-induced Rac activation in T-47D cells. Rac inhibition with β2-chimaerin and N17Rac1, or Rac1 depletion using RNAi, dose-dependently inhibited HRG-induced cyclin D1 mRNA and protein expression and cell proliferation. Rac inhibition also impaired HRG-induced activation of Erk1/2. Inhibition of MEK with U0126 significantly reduced cyclin D1 induction and proliferation by HRG. HRG also induced rapid mRNA and protein expression of p21 while it promotes cell proliferation. Rac inactivation or depletion, or MEK inhibition impaired HRG-induced p21 up-regulation. Moreover, RNAi depletion of p21 impaired HRG-induced cell proliferation. RNAi depletion of ErbB3, ErbB2, or EGFR, but not ErbB4, also impaired HRG-induced cell proliferation. Together, these results indicate that heregulin β1 promotes breast cancer cell proliferation through ErbB receptor/Rac/Erk-dependent cyclin D1 and suggests a paradoxical role for p21 in proliferation.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]