RGD Reference Report - Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats. - Rat Genome Database

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Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats.

Authors: Weroha, SJ  Li, SA  Tawfik, O  Li, JJ 
Citation: Weroha SJ, etal., Carcinogenesis. 2006 Mar;27(3):491-8. Epub 2005 Nov 25.
RGD ID: 2316020
Pubmed: PMID:16311245   (View Abstract at PubMed)
DOI: DOI:10.1093/carcin/bgi278   (Journal Full-text)

A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17beta (E(2))-induced mammary tumorigenesis in female August Copenhagen Irish (ACI) rats. Low serum E(2) levels ( approximately 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 E(2)-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 E(2) treatment. Immunohistochemical analysis of serial sections of focal dysplasias, DCISs and invasive ductal carcinomas showed overexpression of cyclins D1, D3, estrogen receptor-alpha (ERalpha) 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 E(2)-induced MGTs and their binding to cdk4 was significantly elevated. Semi-quantitative reverse transcriptase PCR analysis of the E(2)-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, E(2)-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 E(2)-elicited normal hyperplasia.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Mammary Neoplasms  ISOCcnd3 (Rattus norvegicus)2316020; 2316020mRNA and protein:increased expression:mammary glandRGD 
Experimental Mammary Neoplasms  IEP 2316020mRNA and protein:increased expression:mammary glandRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccnd3  (cyclin D3)

Genes (Mus musculus)
Ccnd3  (cyclin D3)

Genes (Homo sapiens)
CCND3  (cyclin D3)


Additional Information