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Development of hyperplasias, preneoplasias, and mammary tumors in MMTV- c-erbB-2 and MMTV-TGFα transgenic rats

Lookup NU author(s): Dr Barry Davies


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Human cDNAs corresponding to two epidermal growth factor-related products that are overexpressed in human breast cancers, that for c-erbB-2 (HER-2) and for transforming growth factor α (TGFα), have been cloned downstream of the mouse mammary tumor virus (MMTV) long terminal repeat promoter and injected into the pronucleus of fertilized oocytes of Sprague- Dawley rats to produce transgenic offspring. Expression of the transgenic mRNAs is not detectable in mammary tissue from virgin transgenic rats but is detected in mammary tissue from certain lines of mid-pregnant transgenic rats. When two such lines of either type of transgenic rat are subjected to repeated cycles of pregnancy and lactation, they produce, primarily in the mammary glands, extensive pathologies, whereas virgin transgenic rats produce no such abnormalities. Multiparous transgenic female offspring from c-erbB- 2-expressing lines develop a variety of focal hyperplastic and benign lesions that resemble lesions commonly found in human breasts. These lesions include lobular and ductal hyperplasia, fibroadenoma, cystic expansions, and papillary adenomas. More malignant lesions, including ductal carcinoma in situ and carcinoma, also develop stochastically at low frequency. The mammary glands of transgenic females invariably fail to involute fully after lactation. Similar phenotypes are observed in female MMTV-TGFα transgenic rats. In addition, multiparous TGFα-expressing female transgenics frequently develop severe pregnancy-dependent lactating hyperplasias as well as residual lobules of hyperplastic secretory epithelium and genuine lactating adenomas after weaning. These transgenic rat models confirm the conclusions reached in transgenic mice that overexpression of the c-erbB-2 and TGFα genes predisposes the mammary gland to stochastic tumor development.

Publication metadata

Author(s): Davies BR; Platt-Higgins AM; Schmidt G; Rudland PS

Publication type: Article

Publication status: Published

Journal: American Journal of Pathology

Year: 1999

Volume: 155

Issue: 1

Pages: 303-314

Print publication date: 01/07/1999

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: American Society for Investigative Pathology


DOI: 10.1016/S0002-9440(10)65124-3

PubMed id: 10393862


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