Journal Article

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

S.John Weroha, Sara Antonia Li, Ossama Tawfik and Jonathan J. Li

in Carcinogenesis

Volume 27, issue 3, pages 491-498
Published in print March 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi278
Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats

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A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17β (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-α (ERα) 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.

Keywords: ACI, August Copenhagen Irish; ADH, atypical ductal hyperplasia; BC, breast cancer; Cdks, cyclin-dependent kinases; DCIS, ductal carcinoma in-situ; E2, estradiol-17β; ERα, estrogen receptor alpha; H&E, hematoxylin and eosin; MGT, mammary gland tumor; PCR, polymerase chain reaction; PR, progesterone receptor; Q-PCR, quantitative real-time polymerase chain reaction; Rb, retinoblastoma; RT–PCR, reverse transcriptase PCR; SE, standard error

Journal Article.  5421 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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