Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development

Wen Xie, Andrew J. Paterson, Edward Chin, Lisle M. Nabell, Jeffrey E. Kudlow

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

The epidermal growth factor (EGF) system has been thought to play an important role in normal mammary development and carcinogenesis. To study the role of the EGF receptor (EGFR) in mammary development, we developed a transgenic mouse model in which a C-terminal truncated mouse EGFR (EGFR-TR) was expressed in the mouse mammary epithelium under the control of the mouse mammary tumor virus long terminal repeat. The EGFR-TR lacks most of the cytoplasmic domain of the receptor, including the entire protein tyrosine kinase domain. In cultured cells, we show that it acts in a dominant negative manner in EGF-signaled EGFR autophosphorylation. Several lines of mice were characterized and shown to express the transgene at the mRNA and protein levels not only in the mammary gland but also in the salivary glands, epididymis, and prostate. In postpubertal virgin female mice, the expression of the EGFR-TR in the mammary glands was greater than the expression of the endogenous wild type EGFR. In these virgin mice, inhibition in mammary ductal development and a decrease of mammary epithelial DNA synthesis were observed beginning at 5-6 weeks. The inhibition of duct development was most apparent by 15-16 weeks, resulting in a significant defect in ductal branching and outgrowth and an apparent overall decrease in the size of the mammary glands. However, during pregnancy, expression of the endogenous wild type EGFR was markedly increased relative to the EGFR-TR and, at this stage, normal presecretory alveoli developed from the hypoplastic duct tree. Postpartum, normal lactation occurred. Despite EGFR-TR expression in other tissues, no morphological abnormalities were observed. This model demonstrates that the EGFR-TR behaves as a dominant negative regulator of the EGFR system in vivo and that the EGFR system plays an important role in mammary ductal development.

Original languageEnglish (US)
Pages (from-to)1765-1781
Number of pages17
JournalMolecular Endocrinology
Volume11
Issue number12
StatePublished - Jan 1 1997

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Human Mammary Glands
Epidermal Growth Factor Receptor
Transgenic Mice
Breast
Epidermal Growth Factor
Mouse mammary tumor virus
Terminal Repeat Sequences
Epididymis
Cytoplasmic and Nuclear Receptors
Salivary Glands
Transgenes
Lactation
Protein-Tyrosine Kinases
Postpartum Period
Prostate
Cultured Cells
Carcinogenesis
Epithelium

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development. / Xie, Wen; Paterson, Andrew J.; Chin, Edward; Nabell, Lisle M.; Kudlow, Jeffrey E.

In: Molecular Endocrinology, Vol. 11, No. 12, 01.01.1997, p. 1765-1781.

Research output: Contribution to journalArticle

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