Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts

Kokai, Yasuo; Myers, Jeffrey N.; Wada, Takuro; Brown, Valerie I.; LeVea, Charles; Davis, James G.; Dobashi, Kunio; Greene, Mark I.

doi:10.1016/0092-8674(89)90843-x

Cited by 300 publications

(198 citation statements)

References 17 publications

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“…Moreover, ligand stimulated receptors compete for dimer formation with ErbB2 Karunagaran et al, 1996). The distinct signaling activities of each receptor/ligand combination results in diverse cellular responses mediated through heterodimer formation with ErbB2 (DiFiore et al, 1990;Kokai et al, 1989;. Collectively, these results support a signaling paradigm in which ErbB2 ful®lls a role as central mediator of EGFR family signal transduction.…”

Section: Introductionmentioning

confidence: 71%

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

1999

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Overexpression of the receptor tyrosine kinase ErbB2/ HER2/Neu (ErbB2) occurs in 15 ± 40% of human breast cancers. To determine the function of ErbB2 signaling during normal mouse mammary gland development, we expressed a carboxyl-terminal truncated dominant negative allele of ErbB2 (ErbB2DIC) in the developing mouse mammary gland. Despite ErbB2DIC expression within mammary glands of pubescent virgin and pregnant mice, a phenotype was not observed until late in pregnancy. At 1 day post-partum, lactationally active, distended lobuloalveoli failed to form. This phenotype was exaggerated in multiparous females expressing ErbB2DIC. Immunohistochemical staining for ErbB2-DIC revealed a concordance between high levels of ErbB2DIC protein expression and the absence of lactational products within the lumens of ErbB2DIC stained lobuloalveoli. These results demonstrate that ErbB2 signaling is required for proper mammary development and lactation at parturition.

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Section: Introductionmentioning

confidence: 71%

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

1999

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“…In vitro studies (Kokai et al, 1989) suggested that simultaneous overexpression of both EGFR and p185HER-2 acts synergistically. Consequently, we investigated whether patients with EGFR-positive and p185HER-2_positive tumours might have a poorer prognosis than patients with overexpression of either of the receptors or no overexpression at all.…”

Section: Methodsmentioning

confidence: 99%

Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections

Pfeiffer

Clausen²,

Andersen³

et al. 1996

Br J Cancer

128

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Summary The prognostic role of the epidermal growth factor receptor (EGFR) and the related receptor p185HER-2 in lung cancer is as yet undefined. We investigated the immunohistochemical expression of EGFR (monoclonal antibody RI; Amersham) and pl85HER-2 (polyclonal antibody A485; Dako) in cryosections. A total of 186 unselected and systemically untreated patients with non-small-cell lung cancer (NSCLC) diagnosed and treated at Odense University Hospital, Denmark, were included. Median follow-up period was 66 months.EGFR and pl85HER-2 was highly expressed in 55% and 26% of cases respectively. Expression of EGFR was independent of pl85HER-2 expression. The expression of EGFR was higher in squamous cell carcinomas whereas the level of pl85HER-2 staining was higher in adenocarcinomas. Expression of either or both receptors was not correlated with age, histological grading, stage and prognosis. We conclude that immunohistochemical detection of these growth factor receptors failed to demonstrate a prognostic significance in patients operated on for NSCLC.

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“…For example, simultaneous overexpression of both p185c-neu and EGFR was required to induce transformation in NIH:3T3 cells [1]. In addition, mammary tumors derived from transgenic mice engineered to overexpress neu also exhibited co-overexpression of endogenous EGFR [2].…”

Section: Introductionmentioning

confidence: 99%

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

D’Alessio

Luca

Maiello

et al. 2009

Breast Cancer Res Treat

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International audienceTreatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27 mRNA and in the nuclear levels of the p27 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 expression

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Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts

Cited by 300 publications

References 17 publications

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

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

Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections

Effects of the combined blockade of EGFR and ErbB-2 on signal transduction and regulation of cell cycle regulatory proteins in breast cancer cells

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