Epidermal growth factor-induced nuclear factor [Kappa]B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells

The epidermal growth factor (EGF) family of receptors (EGFR) is overproduced in estrogen receptor (ER) negative (-) breast cancer cells. An inverse correlation of the level of EGFR and ER is observed between ER- and ER positive (+) breast cancer cells. A comparative study with EGFR-overproducing ER- and low-level producing ER+ breast cancer cells suggests that EGF is a major growth-stimulating factor for ER- cells. An outline of the pathway for the EGF-induced enhanced proliferation of ER- human breast cancer cells is proposed. The transmission of mitogenic signal induced by EGF-EGFR interaction is mediated via activation of nuclear factor [Kappa]B (NF-[Kappa]B). The basal level of active NF-[Kappa]B in ER- cells is elevated by EGF and inhibited by anti-EGFR antibody (EGFR-Ab), thus qualifying EGF as a NF-[Kappa]B activation factor. NF-[Kappa]B transactivates the cell-cycle regulatory protein, cyclin D1, which causes increased phosphorylation of retinoblastoma protein, more strongly in ER- cells. An inhibitor of phosphatidylinositol 3 kinase, Ly294-002, blocked this event, suggesting a role of the former in the activation of NF-[Kappa]B by EGF. Go6976, a well-characterized NF-[Kappa]B inhibitor, blocked EGF-induced NF-[Kappa]B activation and up-regulation of cell-cycle regulatory proteins. This low molecular weight compound also caused apoptotic death, predominantly more in ER- cells. Thus Go6976 and similar NF-[Kappa]B inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER- breast cancer patients.