Abstract 3010: The role of NF-kappaB in mammary tumor initiation

Abstract

Abstract Nuclear factor kappa B signaling is accepted as a major component of pro-survival signaling within breast cancer cells. However, less is known about how NF-kappaB could contribute to breast tumor initiation. Inflammatory signaling can be activated within the breast by such common factors as obesity, involution following lactation, aging, and psychological stress. Thus, understanding how activated NF-kappaB could lead to the initiation of breast tumors would provide opportunities to develop prevention strategies. We generated a doxycycline-inducible mouse model to study the effects of constitutively active IKK2 on ductal morphogenesis. In this model, Tet-o-cIKK2 mice are crossed with MMTV-rtTA transgenics to target inducible expression specifically to the mammary epithelium. Expression of cIKK2 in transplanted mammary tissue results in enlarged terminal end-buds, increased lateral branching, and intraductal hyperplasia. Transgene induction for only 3 days in a 6 week old female induces filling of ductal lumens, hypercellularity and loss of strict basal/luminal structure. Quantitative PCR of mammary tissue reveals up-regulated markers of macrophage infiltration such as CCL2 and F4/80 and markers of inflammation including Cox-2, TNF-alpha, and CXCL1. Interestingly, constitutive IKK2 activation also results in a decrease in hormone receptor levels (ERα and PR). Immunofluorescent staining shows that activation of classical NF-kappaB increases nuclear p65, as expected. However, nuclear p52 is also increased in transgene positive cells, suggesting that a subset of the effects resulting from activation of classical NF-kappaB are mediated by cross talk with the alternative pathway. Taken together, we find that activation of NF-kappaB in mammary epithelium is sufficient to induce hyperplastic growth and loss of ductal structure. Ongoing studies seek to define what additional factors, such as the right hormonal context, will cause the lesions to progress to malignancy. Citation Format: Whitney Barham, Oleg Tikhomirov, Lianyi Chen, Ryan Ortega, Halina Onishko, Linda Connelly, Fiona E. Yull. The role of NF-kappaB in mammary tumor initiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3010. doi:10.1158/1538-7445.AM2014-3010