The canonical NF-κB pathway is required for formation of luminal mammary neoplasias and is activated in the mammary progenitor population

The role of the canonical NF-kappa B pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of kappa B (I kappa B alpha(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-kappa B DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-kappa B family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-kappa B pathway, but not non-canonical pathway proteins in HER2 | luminal cancers. HER2 | tumors also showed differential regulation of specific NF-kappa B target genes relative to basal and ER+ luminal cancers. Isolation of mammary cell populations enriched for stem and progenitor cell characteristics from an NF-kappa B-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-kappa B whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-kappa B pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias. Oncogene (2009) 28, 2710-2722; doi:10.1038/onc.2009.131; published online 1 June 2009