+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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

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

Bmc Cancer 15: 647

Approximately 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. Our 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. We 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. These 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.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 057113118

Download citation: RISBibTeXText

PMID: 26424146

DOI: 10.1186/s12885-015-1652-8

Related references

Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (clinging ductal carcinoma in situ): A simulator of normal mammary epithelium. Cancer 88(9): 2072-2081, 2000

Tetraspanin CD151 regulates growth of mammary epithelial cells in three-dimensional extracellular matrix: implication for mammary ductal carcinoma in situ. Cancer Research 70(11): 4698-4708, 2010

Aberrant expression of MUC1 mucin in ductal hyperplasia and ductal carcinoma in situ of the breast. International Journal of Cancer 84(5): 466-469, 1999

Correlation of cyclooxygenase-2 and aromatase immunohistochemical expression in invasive ductal carcinoma, ductal carcinoma in situ, and adjacent normal epithelium. Breast Cancer Research and Treatment 95(3): 235-241, 2005

Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. Journal of Cell Biology 156(1): 185-198, 2002

Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration. Bmc Cancer 15: 584, 2015

Expression and mutational status of RON in neoplastic lesions of the breast: analysis of MSP/RON signaling in ductal carcinoma in situ and invasive ductal carcinoma. Apmis 120(5): 358-367, 2012

Cyclin D1 and associated proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. Journal of Pathology 184(4): 396-400, 1998

Cell cycle proteins in mammary ductal carcinoma in situ and atypical ductal hyperplasia. Journal of Pathology 181(Suppl. ): 21A, 1997

Infiltrating ductal carcinoma and ductal carcinoma in situ associated with mammary hamartoma. Breast Journal 12(4): 368-370, 2006

Loss of NF1 results in activation of the ras signaling pathway and leads to aberrant growth in murine and human hematopoietic cells. Blood 86(10 Suppl. 1): 432A, 1995

Fibroblast hepatocyte growth factor promotes invasion of human mammary ductal carcinoma in situ. Cancer Research 69(23): 9148-9155, 2009

Rapamycin inhibits growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ. Clinical Cancer Research 12(8): 2613-2621, 2006