NF-kappaB transcription factors including p65 (RelA), RelB, p105/p50, and p100/p52 play roles in mammary development and tumorigenesis. While most studies have focused on classical NF-kappaB signaling (p65/p50), alternative NF-kappaB signaling is elevated in human primary breast tumors and in human breast cancer cell lines. In addition, we have reported that overexpression of p100 within the mouse mammary epithelium during pregnancy and lactation led to ductal thickening and hyperplastic foci. To determine the contribution of alternative NF-kappaB signaling to mammary development and tumorigenesis, we have developed murine transgenic models that enable us to inducibly express activators or inhibitors of classical or alternative NF-kappaB signaling in the mammary epithelium by adding doxycycline to the drinking water of mice. Modulation of both the classical and alternative pathways will enable us to determine the roles that each arm plays independently or synergistically. Using immunoflourescent staining we have identified distinct patterns of expression of the alternative and classical pathways in mammary epithelium, a previously undescribed phenomenon. Classical p65 signaling was found within the luminal cell population and p100/p52 signaling was observed almost exclusively within the basal cell layer. Upon induction of constitutively activated IKK2 or a dominant negative IKBalpha, two regulators of the classical NF-κB pathway, alterations in branching morphogenesis were observed within the developing virgin gland. These branching phenotypes were associated with a break down in the previously observed classical/alternative signaling pattern, as luminal cells were now expressing low levels of p100/p52. Furthermore, this patterning is disrupted during the development of polyoma middle T oncogene induced tumors in which we also observe alternative signaling no longer confined to the basal layer. Ongoing experiments with our newest transgenic model are designed to determine the effects of inducing alternative signaling, through overexpression of p52, within the mammary epithelium. Our models may reveal novel roles for the alternative NF-kappaB pathway in maintaining the basal/luminal structure of mammary epithelial ducts and connect aberrant p100/p52 signaling to tumor progression, potentially identifying a novel therapeutic target.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5262. doi:1538-7445.AM2012-5262

©2012 American Association for Cancer Research
2012