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

被引:125
作者
Cao, Yixue [1 ]
Luo, Jun-Li [1 ]
Karin, Michael [1 ]
机构
[1] Univ Calif San Diego, Sch Med, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, La Jolla, CA 92093 USA
关键词
breast cancer; NF-kappa B;
D O I
10.1073/pnas.0706728104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:15852 / 15857
页数:6
相关论文
共 32 条
[21]  
PAZOS P, 1992, BREAST CANCER RES TR, V20, P133
[22]   Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties [J].
Ponti, D ;
Costa, A ;
Zaffaroni, N ;
Pratesi, G ;
Petrangolini, G ;
Coradini, D ;
Pilotti, S ;
Pierotti, MA ;
Daidone, MG .
CANCER RESEARCH, 2005, 65 (13) :5506-5511
[23]   Breast cancer stem cells: An overview [J].
Ponti, Dario ;
Zaffaroni, Nadia ;
Capelli, Chiara ;
Daidone, Maria Grazia .
EUROPEAN JOURNAL OF CANCER, 2006, 42 (09) :1219-1224
[24]  
PULLAN SE, 1997, MAMMARY EPITHELIAL C
[25]   Histological differences between ErbB/Ras and wnt pathway transgenic mammary tumors [J].
Rosner, A ;
Miyoshi, K ;
Landesman-Bollag, E ;
Xu, X ;
Seldin, DC ;
Moser, AR ;
MacLeod, CL ;
Shyamala, G ;
Gillgrass, AE ;
Cardiff, RD .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 161 (03) :1087-1097
[26]   C/EBPβ, but not C/EBPα, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland [J].
Seagroves, TN ;
Krnacik, S ;
Raught, B ;
Gay, J ;
Burgess-Beusse, B ;
Darlington, GJ ;
Rosen, JM .
GENES & DEVELOPMENT, 1998, 12 (12) :1917-1928
[27]   CYCLIN D1 PROVIDES A LINK BETWEEN DEVELOPMENT AND ONCOGENESIS IN THE RETINA AND BREAST [J].
SICINSKI, P ;
DONAHER, JL ;
PARKER, SB ;
LI, TS ;
GARDNER, H ;
HASLAM, SZ ;
BRONSON, RT ;
ELLEDGE, SJ ;
WEINBERG, RA .
CELL, 1995, 82 (04) :621-630
[28]   COEXPRESSION OF MMTV/V-HA-RAS AND MMTV/C-MYC GENES IN TRANSGENIC MICE - SYNERGISTIC ACTION OF ONCOGENES INVIVO [J].
SINN, E ;
MULLER, W ;
PATTENGALE, P ;
TEPLER, I ;
WALLACE, R ;
LEDER, P .
CELL, 1987, 49 (04) :465-475
[29]   SPONTANEOUS MAMMARY ADENOCARCINOMAS IN TRANSGENIC MICE THAT CARRY AND EXPRESS MTV/MYC FUSION GENES [J].
STEWART, TA ;
PATTENGALE, PK ;
LEDER, P .
CELL, 1984, 38 (03) :627-637
[30]   EXPRESSION OF THE INT-1 GENE IN TRANSGENIC MICE IS ASSOCIATED WITH MAMMARY-GLAND HYPERPLASIA AND ADENOCARCINOMAS IN MALE AND FEMALE MICE [J].
TSUKAMOTO, AS ;
GROSSCHEDL, R ;
GUZMAN, RC ;
PARSLOW, T ;
VARMUS, HE .
CELL, 1988, 55 (04) :619-625