1. ¹Breast Cancer Research Lab, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
2. ²Department of Pathology and Laboratory Medicine, Ottawa Hospital, Ottawa, Ottawa, Canada
3. ³Ottawa Health Research Institute, Sprott Centre for Stem Cell Research, Ottawa, Ottawa, Canada

Correspondence: MAC Pratt, Department Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, RGN Hall, Ottawa, Ontario, Canada K1H 8M5. E-mail: cpratt@uottawa.ca

Received 15 September 2008; Revised 17 April 2009; Accepted 18 April 2009; Published online 1 June 2009.

Abstract

The role of the canonical NF-B pathway in mammary tumorigenesis was investigated using a transgenic (TG) mouse expressing a dominant-negative inhibitor of B (IB^{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-B DNA-binding activity were detected in mammary luminal lesions, but rarely in squamous metaplasias. Analysis of NF-B family proteins and target genes using microarray data from a cohort of human mammary tumors revealed the expression of a canonical NF-B pathway, but not non-canonical pathway proteins in HER2+ luminal cancers. HER2+ tumors also showed differential regulation of specific NF-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-B-EGFP reporter mouse by fluorescence-activated cell sorting demonstrated that luminal progenitors contain activated NF-B whereas the mammary stem cell-enriched population, does not. Together these data suggest that the canonical NF-B pathway is active in normal luminal progenitor cells before transformation and is required for the formation of mammary luminal-type epithelial neoplasias.