title: Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. Whitney.Barham@vanderbilt.edu.
authors.forename: Whitney
authors.initials: W
authors.lastname: Barham
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. lianyi.chen@vanderbilt.edu.
authors.forename: Lianyi
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. oleg.tikhomirov@vanderbilt.edu.
authors.forename: Oleg
authors.initials: O
authors.lastname: Tikhomirov
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. Hala.Onishko@vanderbilt.edu.
authors.forename: Halina
authors.initials: H
authors.lastname: Onishko
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA. Linda.Gleaves@vanderbilt.edu.
authors.forename: Linda
authors.initials: L
authors.lastname: Gleaves
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA. Thomas.Stricker@vanderbilt.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stricker
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, 1161 21st Ave, Nashville, TN, 37232, USA. Timothy.Blackwell@vanderbilt.edu.|Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, Nashville, TN, 37232, USA. Timothy.Blackwell@vanderbilt.edu.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, 23rd Ave S and Pierce PRB 325, Nashville, TN, 37232, USA. Fiona.Yull@vanderbilt.edu.|Vanderbilt-Ingram Cancer Center, 691 Preston Building, 2220 Pierce Ave, Nashville, TN, 37232, USA. Fiona.Yull@vanderbilt.edu.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D009928:Organ Specificity / Q000235:genetics; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D051550:I-kappa B Kinase