A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation.

Fowler, Kerry J.; Walker, Francesca; Alexander, Warren S.; Hibbs, Margaret L.; Nice, Edouard C.; Böhmer, Ralph M.; Mann, G. Bruce; Thumwood, Cassandra M.; Maglitto, Rosemarie; Danks, Janine A.

doi:10.1073/pnas.92.5.1465

Cited by 202 publications

(138 citation statements)

References 30 publications

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“…For example, the mammary-specific knockout of ErbB4 resulted in a profound defect in functional differentiation of mammary epithelium (Long et al, 2003). Moreover, the waved-2 mice, which harbor an impaired EGFR allele, also have lactational defects (Fowler et al, 1995). Taken together with our observations, these data suggest that ErbB4 homodimers or heterodimers consisting of EGFR or ErbB3 but not ErbB2 are important EGFR family receptor combinations for functional differentiation and lactation.…”

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confidence: 70%

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Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth

2004

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The ErbB2 receptor tyrosine kinase has been implicated as a critical growth factor receptor in both normal development and cancer. Amplification and overexpression of this receptor is observed in 20-30% of all human breast cancers and is inversely correlated with patient survival. Studies with transgenic mice have established that elevated expression of erbB2 in mammary epithelium can directly induce mammary carcinomas. Although these studies confirmed a role for ErbB2 in breast cancer induction, the precise role of ErbB2 in normal mammary gland development remained to be elucidated due to the embryonic lethality associated with the null mutation. Here, we demonstrate that the mammary-specific ablation of erbB2 through Cre-mediated recombination leads to a striking ductal elongation defect. In addition to the observed elongation defect, we noted that branching in the adult mammary gland was also reduced. Despite these perturbations in virgin mammary gland morphogenesis, targeted disruption of erbB2 had little impact on the ability of these animals to lactate. Taken together, these observations indicate that erbB2 plays a critical role in the initial stages of mammary gland morphogenesis. Oncogene (2005) 24, 932-937.

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supporting

confidence: 70%

“…For example, waved-2 mice carrying a kinase impaired EGFR allele exhibit comparable ductal defects (Fowler et al, 1995). However in contrast to cell autonomous requirement for ErbB2 function, transplantation of EGFR null tissues has revealed that EGFR functions primarily in the stroma during the phase of ductal outgrowth (Sebastian et al, 1998).…”

mentioning

confidence: 99%

Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth

2004

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“…There are a number of observations that favour the correlation between EGFR affinity and biological effect (Defize et al, 1989;Bellot et al, 1990). Others have found a similar correlation between the affinity state of the EGFR and proliferative effect after growth factor administration (Fowler et al, 1995). It has been shown that a T → G point mutation in the EGFR at residue 743 results in the wa-2 phenotype (Luetteke et al, 1994;Fowler et al, 1995), which is characterized by loss of high-affinity EGFRs and a requirement for a 20-fold higher concentration of EGF to achieve the same effect on DNA replication as seen with the cells bearing wild-type EGFRs (Fowler et al, 1995).…”

Section: Discussionmentioning

confidence: 97%

Amphiregulin acts as an autocrine growth factor in two human polarizing colon cancer lines that exhibit domain selective EGF receptor mitogenesis

et al. 1999

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Summary Colonic enterocytes, like many epithelial cells in vivo, are polarized with functionally distinct apical and basolateral membrane domains. The aims of this study were to characterize the endogenous epidermal growth factor (EGF)-like ligands expressed in two polarizing colon cancer cell lines, HCA-7 Colony 29 (HCA-7) and Caco-2, and to examine the effects of cell polarity on EGF receptor-mediated mitogenesis. HCA-7 and Caco-2 cells were grown on plastic, or as a polarized monolayer on Transwell filters. Cell proliferation was measured by 3 H-thymidine incorporation and EGF receptor (EGFR) binding was assessed by Scatchard analysis. EGFR ligand expression was determined by Northern blot analysis, reverse transcription polymerase chain reaction, metabolic labelling and confocal microscopy. We found that amphiregulin (AR) was the most abundant EGFR ligand expressed in HCA-7 and Caco-2 cells. AR was localized to the basolateral surface and detected in basolateral-conditioned medium. Basolateral administration of neutralizing AR antibodies significantly reduced basal DNA replication. A single class of high-affinity EGFRs was detected in the basolateral compartment, whereas the apical compartment of polarized cells, and cells cultured on plastic, displayed two classes of receptor affinity. Basolateral administration of transforming growth factor alpha (TGF-α) or an EGFR neutralizing antibody also resulted in a dose-dependent stimulation or attenuation, respectively, of DNA replication. However, no mitogenic response was observed when these agents were added to the apical compartment or to confluent cells cultured on plastic. We conclude that amphiregulin acts as an autocrine growth factor in HCA-7 and Caco-2 cells, and EGFR ligand-induced proliferation is influenced by cellular polarity.

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“…Notably, in vivo analyses revealed that mammary development was impaired in waved-2 mice that harbored a mutant (kinase-deficient) EGFR on all cells [21,22] and similarly impaired in transgenic mice that expressed a dominant-negative EGFR on their mammary epithelial cells alone [23], suggesting that epithelial EGFR played a key role. However, EGFR is also abundant within the mammary stroma [24,25].…”

Section: Stromal Egfr Is Required For Mammary Developmentmentioning

confidence: 99%

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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A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation.

Cited by 202 publications

References 30 publications

Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth

Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth

Amphiregulin acts as an autocrine growth factor in two human polarizing colon cancer lines that exhibit domain selective EGF receptor mitogenesis

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

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