ErbB2 is required for ductal morphogenesis of the mammary gland

Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2005; 101(49):17138-43. DOI: 10.1073/pnas.0407057101
Source: PubMed


The ERBB2/HER2/NEU receptor tyrosine kinase gene is amplified in up to 30% of human breast cancers. The frequent and specific selection of this receptor kinase gene for amplification in breast cancer implies that it has important normal functions in the mammary gland. To investigate the functions of ErbB2 during normal mouse mammary gland development, we transplanted mammary buds from genetically rescued ErbB2(-/-) embryos that express ErbB2 in the cardiac muscle. ErbB2(-/-) mammary buds transplanted to a wild-type mammary fat pad support outgrowth of an epithelial tree that advances only slowly through the mammary fat pad at puberty. This penetration defect is associated with structural defects in terminal end buds, characterized by a decrease in body cell number, an increased presence of cap-like cells in the prelumenal compartment, and the presence of large luminal spaces. Lobuloalveolar development was not affected in glands that developed from ErbB2(-/-) transplanted tissue. The results may have implications for the aggressive phenotypes associated with ERBB2-overexpressing mammary carcinomas.

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    • "ErbB3 and ErbB4 are normally absent during early ductal development (Schroeder and Lee 1998), but might have been up-regulated in the absence of EGFR. Moreover, epithelial expression of ErbB2 is necessary for ductal extension (Jackson-Fisher et al. 2004; Andrechek et al. 2005). "
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    • "Exogenous estradiol induces tyrosine phosphorylation of EGFR as well as ErbB2 in ovariectomized mice, which is also observed in pubertal mammary glands (Sebastian et al. 1998). Intriguingly, ErbB2, which heterodimerizes with EGFR or other ErbB receptors, is required in the epithelium for normal ductal development (Jackson-Fisher et al. 2004; Andrechek et al. 2005), whereas ErbB4 is required for lobuloalveologenesis during pregnancy (Tidcombe et al. 2003). Factors that play important local functions in maintaining the TEB or ductal morphology include netrin-1 and its receptor neogenin (Srinivasan et al. 2003) and a cell surface morphogen epimorphin (Radisky et al. 2003). "
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    • "Measurements of total ductal outgrowth length on whole glands (no half glands) and branch density (whole and half glands) were taken as described in [26], except with the use of ImageJ imaging software (Wayne Rasband, National Institutes of Health, Bethesda, Maryland, USA). Briefly, the total ductal outgrowth in digital images of glands was determined by drawing a line from the one edge of furthest ductal outgrowth to the opposite edge of furthest ductal outgrowth, and measuring the length of that line in arbitrary units. "
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