Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation

Jones, Frank E.; Stern, David F.

doi:10.1038/sj.onc.1202698

Cited by 106 publications

(68 citation statements)

References 46 publications

(47 reference statements)

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“…As has been noted, stromal EGFR regulates mammary development, yet ductal development is also impaired in transgenic mice that express dominant-negative EGFR in the epithelium alone [23]. Although this could reflect downregulation of epithelial ErbB2 signaling, the mammary-targeted expression of a dominant-negative ErbB2 transgene causes alveolar defects that only become apparent in dams at parturition [76]. Nevertheless, genetically rescued (cardiac ErbB2 transgenic) ErbB2-null mammary glands do exhibit delayed ductal penetration and TEB defects when they are transplanted to cleared wild-type mammary fat pads, though they do eventually catch up and undergo lactational differentiation [77].…”

Section: Does Egfr Affect Ductal Development Alone or In Concert Withmentioning

confidence: 92%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Section: Does Egfr Affect Ductal Development Alone or In Concert Withmentioning

confidence: 92%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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“…4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance correlates with poor prognosis, and it is, therefore, an important target for physiologic investigation and therapeutic intervention. 5 It has been shown that treatment with the pineal indole hormone melatonin inhibits the development of mammary gland tumorigenesis both in vitro and in vivo.…”

Section: Abstract: Peptide; Her-2/neu; Transgenic Mice; Mammary Cancermentioning

confidence: 99%

Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

Anisimov

Khavinson

Provinciali

et al. 2002

Intl Journal of Cancer

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Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalonா (Ala-Glu-Asp-Gly) or with the peptide Vilonா (Lys-Glu) in a single dose of 1 g/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalontreated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon-than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/ neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide. © 2002 Wiley-Liss, Inc. Key words: peptide; HER-2/neu; transgenic mice; mammary cancerBreast cancer is one of the most common cancers and is a leading cause of mortality in women. 1,2 The HER-2/neu oncogene encodes a 185 kDa (p 185) receptor protein belonging to the epidermal growth factor receptor family involved in organogenesis and epithelial differentiation. 3 Amplification and mutation of HER-2/neu plays a pathogenetic role in several malignancies, including carcinoma of the breast, ovary and uterus. 4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance correlates with poor prognosis, and it is, therefore, an important target for physiologic investigation and therapeutic intervention. 5 It has been shown that treatment with the pineal indole hormone melatonin inhibits the development of mammary gland tumorigenesis both in vitro and in vivo. [7][8][9][10] It was also shown that the polypeptide pineal preparation Epithalamin inhibits both the growth of transplantable mammary tumors and the development of spontaneous mammary tumors in female C3H/Sn and SHR mice and mammary carcinogenesis induced by 7,12-dimethylbenzanthracene mammary tumors or by total-body X-ray irradiation in female rats. 11-13 Clinical use of Epithalamin was shown to be effective for the treatment of ovarian disturbances and of some types of cancer, breast cancer included. 14 However, the in vivo use of Epithalamin has been rathe...

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“…Five-micrometer sections were cut and stained with hematoxylin͞eosin (H&E) (17). Twelve ϩ͞ϩ, four ϩ͞Ϫ, and seven Ϫ͞Ϫ gland outgrowths were analyzed 4 weeks posttransplant; six ϩ͞ϩ or ϩ͞Ϫ and nine Ϫ͞Ϫ glands at 7 weeks posttransplant; one ϩ͞ϩ and two Ϫ͞Ϫ glands at 13 weeks posttransplant; and five ϩ͞ϩ or ϩ͞Ϫ and four Ϫ͞Ϫ glands at 1 day postpartum (uniparous and multiparous).…”

Section: Methodsmentioning

confidence: 99%

“…The phenotype of transgenic mice expressing a truncated dominant-negative ErbB2 in adult females, which retards late mammary development and lactation, has suggested an important role for ErbB2 in final stages of lactational differentiation (17). However, the ability of ErbB2 to form heteromers with other EGF family receptors means that the dominant-negative effects may be mediated through inactivation of endogenous ErbB2, other ErbBs, or some combination.…”

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confidence: 96%

ErbB2 is required for ductal morphogenesis of the mammary gland

Jackson-Fisher

Bellinger

Ramabhadran

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The ERBB2͞HER2͞NEU 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.development ͉ terminal end bud ͉ HER2 ͉ EGF

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Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation

Cited by 106 publications

References 46 publications

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

ErbB2 is required for ductal morphogenesis of the mammary gland

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