Carcinogenesis Advance Access originally published online on November 25, 2005
Carcinogenesis 2006 27(3):491-498; doi:10.1093/carcin/bgi278
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats
Hormonal Carcinogenesis Laboratory, Department of Pharmacology, Toxicology, and Therapeutics and 1 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
* To whom correspondence should be addressed at: Department of Pharmacology, Mail Stop 1018, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA Email: jli1{at}kumc.edu
A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17ß (E2)-induced mammary tumorigenesis in female August Copenhagen Irish (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 cyclins D1 (24-fold), D3 (9-fold) and cdk4 (3-fold) expression compared with age-matched untreated controls. Small focal dysplasias with large, pale staining nuclei were commonly seen at 3–3.6 months, large focal dysplasias, including atypical ductal hyperplasia at 3.6–4.3 months, ductal carcinoma in-situ (DCISs) at 4.3–5.0 months, and 100% incidence of invasive ductal BC/frank tumors at 5–6 months were detected after E2 treatment. Immunohistochemical analysis of serial sections of focal dysplasias, DCISs and invasive ductal carcinomas showed overexpression of cyclins 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 <1–5% of resting and normal hyperplastic breast cells staining positive. The kinase activity for cyclins 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 cyclins 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 cyclins D1 and D3, thus contributing to a distinct growth advantage of these pre-neoplasias relative to E2-elicited normal hyperplasia.
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