The nuclear factor kappa B (NF-kappa B): A potential therapeutic target for estrogen receptor negative breast cancers

The effect of a kinase inhibitor Go6796 on growth of epidermal growth facto r (EGF)-stimulated estrogen receptor negative (ER-) breast cancer cells in vivo and role of nuclear factor kappa B (NF-kappaB) on tumorogenesis have b een investigated. This was studied in an animal model by implanting ER- mou se mammary epithelial tumor cells (CSMLO) in syngeneic A-J mice. (i) Local administration of Go6976 an inhibitor of protein kinases C alpha and beta i nhibited growth of tumors and caused extensive necrotic degeneration and re gression of the tumors without causing any microscopically detectable damag e to the vital organs liver and lung. (ii) Stable expression of dominant-ne gative mutants of the beta subunit (dnlkk beta) of the inhibitory kappa B ( I kappaB) kinase (dnlkk) that selectively blocked activation of NF-kappaB c aused loss of tumorigenic potential of CSMLO cells. Stable expression of dn lkk beta also blocked phorbol 12-myristate 13-acetate (PMA)-induced activat ion of NF-A and overexpression of cyclin D1, concomitantly with the loss or reduced tumorigenic potential of these cells. Thus, results from in vivo a nd in vitro experiments strongly suggest the involvement of NF-kappaB in ER - mammary epithelial cell-mediated tumorigenesis. We propose that blocking NF-kappaB activation not only inhibits cell proliferation, but also antagon izes the antiapoptotic role of this transcription factor in ER- breast canc er cells. Thus, NF-kappaB is a potential target for therapy of EGFR family receptor-overexpressing ER- breast cancers.