The canonical NF-kappaB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population.
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.
Pratt
M A C
MA
Breast Cancer Research Lab, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. cpratt@uottawa.ca
Tibbo
E
E
Robertson
S J
SJ
Jansson
D
D
Hurst
K
K
Perez-Iratxeta
C
C
Lau
R
R
Niu
M Y
MY
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology; D051927:CD24 Antigen / Q000032:analysis; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis; D039503:Integrin alpha6 / Q000032:analysis; D008325:Mammary Neoplasms, Experimental / Q000209:etiology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000032:analysis
D015127:9,10-Dimethyl-1,2-benzanthracene; D051927:CD24 Antigen; D051550:I-kappa B Kinase; D039503:Integrin alpha6; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D051996:Transcription Factor RelA; C524056:Erbb2 protein, mouse