Lani
09-25-2007, 06:47 AM
lots of big words, but basically they are discovering what drives the cancer stem cells responsible for her2+ bc to make new tumors and what might be causing her2+ bc in the first place(important for prevention and treatment)
note especially the reference to "inability to establish secondary tumors" ie, the cells are no longer able to cause metastases, lose their malignant potential
1: Proc Natl Acad Sci U S A. 2007 Sep 21; [Epub ahead of print]
I{kappa}B kinase {alpha} kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells.
Cao Y, Luo JL, Karin M.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723.
NF-kappaB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-kappaB in breast carcinogenesis is unknown. Ikkalpha(AA/AA) "knockin" mice in which activation of IkappaB kinase alpha (IKKalpha) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKalpha 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 IKKalpha in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The Ikkalpha(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-Ha-ras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKalpha 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. IKKalpha may represent a novel and specific target for treatment of ErbB2-positive breast cancer.
PMID: 17890319 [PubMed - as supplied by publisher]
note especially the reference to "inability to establish secondary tumors" ie, the cells are no longer able to cause metastases, lose their malignant potential
1: Proc Natl Acad Sci U S A. 2007 Sep 21; [Epub ahead of print]
I{kappa}B kinase {alpha} kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells.
Cao Y, Luo JL, Karin M.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723.
NF-kappaB is constitutively active in many solid tumors, including breast cancer. However, the role of NF-kappaB in breast carcinogenesis is unknown. Ikkalpha(AA/AA) "knockin" mice in which activation of IkappaB kinase alpha (IKKalpha) is prevented by replacement of activation loop serines with alanines exhibit delayed mammary gland growth during pregnancy, because IKKalpha 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 IKKalpha in mammary carcinogenesis induced by oncogenes or a chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The Ikkalpha(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-Ha-ras-induced cancer, although both oncogenes rely on cyclin D1. Strikingly, primary Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells exhibited diminished self-renewal capacity, resulting in the inability to establish secondary tumors. Ikkalpha(AA/AA)/MMTV-c-neu carcinoma cells underwent premature senescence when cultured under conditions used for propagation of mammary gland stem cells. Thus, IKKalpha 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. IKKalpha may represent a novel and specific target for treatment of ErbB2-positive breast cancer.
PMID: 17890319 [PubMed - as supplied by publisher]