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 kappaB (NF-kappaB). The basal level of active NF-kappaB in ER- cells is elevated by EGF and inhibited by anti-EGFR antibody (EGFR-Ab), thus qualifying EGF as a NF-kappaB activation factor. NF-kappaB 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-kappaB by EGF. Go6976, a well-characterized NF-kappaB inhibitor, blocked EGF-induced NF-kappaB 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-kappaB inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER- breast cancer patients.
Biswas
D K
DK
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. biswas@mbcrr.harvard.edu
Cruz
A P
AP
Gansberger
E
E
Pardee
A B
AB
D001943:Breast Neoplasms / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002453:Cell Cycle; D019938:Cyclin D1 / Q000378:metabolism / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D007211:Indoles; D016328:NF-kappa B; D011960:Receptors, Estrogen; C081021:Go 6976; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors