Carcinogenesis Advance Access published online on November 25, 2005
Carcinogenesis, doi:10.1093/carcin/bgi278
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1 Hormonal Carcinogenesis Laboratory, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160
* To whom correspondence should be addressed. A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclin D1 and D3 was examined during estradiol-17
Received May 6, 2005
Revised November 14, 2005
Accepted November 20, 2005
CANCER BIOLOGY
Overexpression of cyclin D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats
S. John Weroha 1,
Sara Antonia Li 1,
Ossama Tawfik 2,
and
Jonathan J. Li 1 *
2 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160
Jonathan J. Li, E-mail: jli1{at}kumc.edu
Abstract 
(E2)-induced mammary tumorigenesis in female ACI rats. Low serum E2 levels (
60-120 pg/ml) were sufficient to induce mammary gland tumors (MGTs) that remarkably resemble human ductal breast cancer (BC) at the histopathologic and molecular levels. Western blot analysis of the E2-induced MGTs revealed a marked rise in cyclin D1 (24.0-fold), D3 (9.0-fold), and cdk4 (3.0-fold) expression compared to age-matched untreated controls. Small focal dysplasias with large, pale staining nuclei were commonly seen at 3.0-3.6 mo., large focal dysplasias, including atypical ductal hyperplasia at 3.6-4.3 mo., ductal carcinoma in-situ (DCISs) at 4.3-5.0 mo., and 100% incidence of invasive ductal BC/frank tumors at 5.0-6.0 mo. were detected after E2-treatment. Immunohistochemical analysis of serial sections of focal dysplasias, ductal carcinoma in-situ (DCISs), and invasive ductal carcinomas showed over-expression of cyclin D1, D3, estrogen receptor-
(ER), and progesterone receptor (PR). However, cyclin D3 expression, unlike D1, was confined essentially to early pre-malignant lesions (focal dysplasias and DCISs) and primary MGTs with less than 1-5% of resting and normal hyperplasic breast cells staining positive. The kinase activity for cyclin D1 and D3, using retinoblastoma (Rb) as a substrate, in E2-induced MGTs and their binding to cdk4 was significantly elevated. Semi-quantitative reverse transcriptase PCR analysis of the E2-induced MGTs exhibited increased expression of cyclin D1 (2.9-fold) and D3 (1.4-fold) mRNA, indicating that their elevated protein expression was due in part to an increase in mRNA transcription. However, when analyzed by quantitative real-time Q-PCR, these genes were not amplified. These data indicate that in female ACI rat mammary glands, E2-induced pre-malignant lesions differentially and selectively express cyclin D1 and D3, thus contributing to a distinct growth advantage of these pre-neoplasias relative to E2-elicited normal hyperplasia.
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