IκB kinase a kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells

NF-kappa B is constitutively active in many solid tumors, including breast cancer. However, the role of NF-kappa B in breast carcinogenesis is unknown. Ikk alpha(AA/AA) "knockin" mice in which activation of I kappa B kinase a (111(11(a) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKK alpha activity is required for cyclin D1 induction and proliferation of lobuloalveolar epithelial cells. Given the role of cyclin D1 in breast and mammary cancer, we examined involvement of IKKa in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The Ikk alpha(AA) mutation retarded tumor development in response to either 7,12-dimethylbenzaanthracene or the MMTV-c-neu (ErbB2/Her2) transgene but had no effect on MMTV-v-Haras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary Ikk alpha(AA/AA) /MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. Ikk alpha(AA/AA)/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKa is not only a regulator of mammary epithelial proliferation, but is also an important contributor to ErbB2-induced oncogenesis, providing signals that maintain mammary tumor-initiating cells. IKKa may represent a novel and specific target for treatment of ErbB2-positive breast cancer.