title: Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden.
abstract: The transcription factor nuclear factor kappa B (NF-κB) is activated in human breast cancer tissues and cell lines. However, it is unclear whether NF-κB activation is a consequence of tumor formation or a contributor to tumor development. We developed a doxycycline (dox)-inducible mouse model, termed DNMP, to inhibit NF-κB activity specifically within the mammary epithelium during tumor development in the polyoma middle T oncogene (PyVT) mouse mammary tumor model. DNMP females and PyVT littermate controls were treated with dox from 4 to 12 weeks of age. We observed an increase in tumor latency and a decrease in final tumor burden in DNMP mice compared with PyVT controls. A similar effect with treatment from 8 to 12 weeks indicates that outcome is independent of effects on postnatal virgin ductal development. In both cases, DNMP mice were less likely to develop lung metastases than controls. Treatment from 8 to 9 weeks was sufficient to impact primary tumor formation. Inhibition of NF-κB increases apoptosis in hyperplastic stages of tumor development and decreases proliferation at least in part by reducing Cyclin D1 expression. To test the therapeutic potential of NF-κB inhibition, we generated palpable tumors by orthotopic injection of PyVT cells and then treated systemically with the NF-κB inhibitor thymoquinone (TQ). TQ treatment resulted in a reduction in tumor volume and weight as compared with vehicle-treated control. These data indicate that epithelial NF-κB is an active contributor to tumor progression and demonstrate that inhibition of NF-κB could have a significant therapeutic impact even at later stages of mammary tumor progression.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232-6838, USA.
authors.forename: L
authors.initials: L
authors.lastname: Connelly
authors.forename: W
authors.initials: W
authors.lastname: Barham
authors.forename: H M
authors.initials: HM
authors.lastname: Onishko
authors.forename: T
authors.initials: T
authors.lastname: Sherrill
authors.forename: L A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: T S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: F E
authors.initials: FE
authors.lastname: Yull
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004318:Doxycycline / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D016328:NF-kappa B; D004318:Doxycycline