Early Molecular and Cellular Events in 7,12-Dimethylbenz(a)-anthracene (DMBA)
Induced Rat Mammary Cancer
J.O. Johnston, J.H. Carter, H.W. Carter, R.E. Richmond, G. Talaska, D. Warshawsky.
1Wood Hudson Cancer Research Laboratory, 931 Isabella St., Newport, KY 41071(JOJ,
JHC, HWC), Northern Kentucky University, Highland Heights, KY 41099(RER),
and University of Cincinnati College of Medicine, School of Environmental
Health, Cincinnati, OH 45229(GT, DW)
ABSTRACT
The classical animal model for carcinogen induced mammary tumors was utilized
to quantitatively and qualitatively determine DMBA-DNA adducts, associated
alterations in expression of molecular biomarkers and related early changes
in histology and morphology of developing mammary glands and/or tumors.
Female 50-day old Sprague Dawley rats were given orally 20 mg DMBA or vehicle.
Animals were sacrificed at 1 or 7 days and 1 or 6 months later for determination
of tumor incidence, morphology and biomarker profiles. For comparative evaluation
of early development, mammary glands were studied in groups of untreated
rats from 45-80 days old. DNA adducts were determined by 32P-postlabeling
which revealed a major and 2 minor DMBA products. Adduct concentrations
were related to subsequent tumor incidence with adduct levels in thoracic
glands exceeding those of abdominal glands by 2-fold at 1 and 7 days after
DMBA. At Day 7, glands exhibited decreased TGF-B1, and c-Jun expression,
and altered morphologic characteristics. Volume percent of mammary glands
occupied by lobules were reduced by 80% and 88% at 7 days and 30 days. At
5-6 months following DMBA, lobular volume remained reduced by 68% in only
those rats without tumors. Lobular volume had increased 175% over controls
in rats with inarticulate tumors (66/67) of which 66% were carcinoma or
nodular hyperplasia with atypia. Cell proliferation, as indicated by intense
PCNA labeling, was increased in nuclei of tumors and adjacent breast tissue,
suggesting tumor-related stimulation of localized lobular development.
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