Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ

BMC Cancer

Research Article

Halina Onishko¹  Oleg Tikhomirov¹  Whitney Barham¹  Lianyi Chen¹  Fiona E. Yull²  Linda Gleaves³  Timothy S. Blackwell⁴  Thomas P. Stricker⁵ 

[1] Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, 37232, Nashville, TN, USA;Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, 37232, Nashville, TN, USA;Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, 37232, Nashville, TN, USA;Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, 37232, Nashville, TN, USA;Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, 37232, Nashville, TN, USA;Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, 37232, Nashville, TN, USA;Department of Pathology, Vanderbilt University Medical Center, 1161 21st Ave, 37232, Nashville, TN, USA;

关键词: Nuclear factor kappa-B;    Mammary;    Inflammation;    Hyperplasia;    Ductal carcinoma in situ;    Mucin 1;   

DOI  :  10.1186/s12885-015-1652-8

 received in 2015-02-11, accepted in 2015-09-15,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundApproximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling. However, the contributions of NF-κB signaling to tumor initiation are less well understood. Aberrant up-regulation of NF-κB activity, either systemically or locally within the breast, could occur due to a variety of commonly experienced stimuli such as acute infection, obesity, or psychological stress. In this study, we seek to determine if activation of NF-κB in mammary epithelium could play a role in the formation of hyperplastic ductal lesions.MethodsOur studies utilize a doxycycline-inducible transgenic mouse model in which constitutively active IKKβ is expressed specifically in mammary epithelium. All previously published models of NF-κB modulation in the virgin mammary gland have been constitutive models, with transgene or knock-out present throughout the life and development of the animal. For the first time, we will induce activation at later time points after normal ducts have formed, thus being able to determine if NF-κB activation can promote pre-malignant changes in previously normal mammary epithelium.ResultsWe found that even a short pulse of NF-κB activation could induce profound remodeling of mammary ductal structures. Short-term activation created hyperproliferative, enlarged ducts with filled lumens. Increased expression of inflammatory markers was concurrent with the down-regulation of hormone receptors and markers of epithelial differentiation. Furthermore, the oncoprotein mucin 1, known to be up-regulated in human and mouse DCIS, was over-expressed and mislocalized in the activated ductal tissue.ConclusionsThese results indicate that aberrant NF-κB activation within mammary epithelium can lead to molecular and morphological changes consistent with the earliest stages of breast cancer. Thus, inhibition of NF-κB signaling following acute inflammation or the initial signs of hyperplastic ductal growth could represent an important opportunity for breast cancer prevention.

【 授权许可】

CC BY   
© Barham et al. 2015