The canonical NF-kappaB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population. Oncogene 2009 Jul 30;28(30):2710-22
Date
06/02/2009Pubmed ID
19483731DOI
10.1038/onc.2009.131Scopus ID
2-s2.0-68149164966 (requires institutional sign-in at Scopus site) 70 CitationsAbstract
The role of the canonical NF-kappaB pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of kappaB (IkappaBalpha(SR (S32A/S36A))) in the mammary gland under the control of the mouse mammary tumor virus promoter (MMTV). TG and control mice were subjected to a chemical carcinogenesis protocol. Hyperkeratinized squamous metaplasias (cytokeratin-6+/p63+) sometimes with a basaloid island component, were found in both TG and control mice whereas luminal (cytokeratin-19+/MUC1+) ErbB2+ papillary and adenomatous lesions developed almost exclusively in control mice. p65/RelA- and NF-kappaB DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-kappaB family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-kappaB pathway, but not non-canonical pathway proteins in HER2+ luminal cancers. HER2+ tumors also showed differential regulation of specific NF-kappaB target genes relative to basal and ER+ luminal cancers. Isolation of mammary cell populations enriched for stem and progenitor cell characteristics from an NF-kappaB-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-kappaB whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-kappaB pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias.
Author List
Pratt MA, Tibbo E, Robertson SJ, Jansson D, Hurst K, Perez-Iratxeta C, Lau R, Niu MYAuthor
Kathleen M. Bone PhD Associate Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
9,10-Dimethyl-1,2-benzanthraceneAnimals
Breast Neoplasms
CD24 Antigen
Humans
I-kappa B Kinase
Integrin alpha6
Mammary Neoplasms, Experimental
Mammary Tumor Virus, Mouse
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B
Neoplastic Stem Cells
Receptor, ErbB-2
Signal Transduction
Transcription Factor RelA