Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines

Gollamudi, Murthy; Nethery, David; Wang, Zhibin; Kern, Jeffrey A.

doi:10.1016/j.lungcan.2003.08.027

Cited by 52 publications

(48 citation statements)

References 24 publications

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“…In addition, HRG is known to be secreted by several tumor cells including breast cancer and melanoma cells. [30][31][32] Taken together, these findings suggest that HRG-induced ErbB3 activation in the primary tumor is essential for intravasation and subsequent extravasation into the target organ, and that exposure to HRG at the primary site is essential for the acquisition of metastatic activity. The HRG gene family has 4 members; HRG-1, HRG-2, HRG-3 and HRG-4, of which a multitude of different isoforms are synthesized by alternative exon splicing, showing various tissue distribution and biological activities.…”

Section: Discussionmentioning

confidence: 87%

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Ueno

Sakurai

Tsunoda

et al. 2008

Intl Journal of Cancer

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ErbB3 receptor tyrosine kinase has been shown to induce tumor progression in several types of cancer through heterodimerization with ErbB2. However, the role of ErbB3 and its ligand heregulin (HRG) in tumor metastasis remains poorly understood. In the present study, we tried to clarify their contributions to the metastasis of ErbB3-overexpressing B16-BL6 melanoma cells. Stimulation with HRG induced phosphorylation of ErbB3 and metastatic properties including MMP-9 expression, invasion, adhesion and experimental lung metastasis in vivo. These cellular responses were blocked by inhibiting the tyrosine kinase activity of EGFR with PD153035. In addition, phosphorylation of EGFR was rapidly induced by HRG, suggesting that EGFR is a possible heterodimeric counterpart of ErbB3. RNA interference demonstrated that subcutaneous tumor growth and angiogenesis was attenuated by inactivation of ErbB3 in cancer cells. Although experimental pulmonary metastasis was not affected by the knockdown of ErbB3, spontaneous metastasis was, even when primary tumors in the foot pad were amputated at a similar size. These results indicate that HRG-induced activation of ErbB3 via EGFR promotes tumor growth and metastasis of melanoma cells. ' 2008 Wiley-Liss, Inc.Key words: ErbB3; EGFR; heregulin; metastasis; melanoma The receptor tyrosine kinase (RTK) family of ErbBs forms part of a complex signal cascade modulating cell proliferation, survival and adhesion. The family comprises 4 homologous receptors, EGFR, ErbB2, ErbB3 and ErbB4, which form homodimers or heterodimers to initiate intracellular signaling in response to their ligands. EGFR and ErbB2 have recently been focused on the molecular targeted therapy of cancer, because overexpression, amplification and mutations are involved in carcinogenesis and the progression of several types of cancer including metastasis. 1-3Tyrosine kinase inhibitors and neutralizing monoclonal antibodies against these receptors are clinically approved for the treatment of nonsmall cell lung cancer (NSCLC) and breast cancer. In addition to tumorigenesis, these receptors have also been shown to contribute to metastasis. 4,5 In spite of no high affinity ligand for ErbB2 and the inactive kinase domain of ErbB3, the ErbB2/ErbB3 heterodimer is believed to be the most biologically active and tumorigenic of the possible heterodimer complexes of ErbB3.6-8 It has been reported that 20-30% of human breast cancers overexpress ErbB2.9 ErbB3 expression is also reported to be closely associated with relapse-free and overall survival and is associated with a high risk of metastasis among patients with NSCLC.10 In breast cancer ErbB3-dependent signaling through the ErbB3/ErbB2 heterodimer contributes to metastasis by enhancing tumor cell invasion and intravasation. 11In comparison to the ErbB2/ErbB3 heterodimer, little is known about the tumorigenic and metastatic functions of the EGFR/ ErbB3 heterodimer. In addition, while the ErbB3 in other cancers is being studied, the role of ErbB3 in the metastasis of melanoma cells re...

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Section: Discussionmentioning

confidence: 87%

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Ueno

Sakurai

Tsunoda

et al. 2008

Intl Journal of Cancer

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“…It is known that ErbB2 and ErbB3 dimerize to produce a highaffinity receptor for neuregulin-1. Because production and secretion of neuregulin-1 have been reported in many human lung cancer cell lines (28), it is very likely that neuregulin-1 or neuregulin isoform is secreted from PC-14 cells and thereafter activates the ErbB2/ErbB3 heterodimer in an autocrine fashion. This likelihood is supported by the finding that ErbB3 phosphorylation was increased on B4G7 addition and abrogated in the presence of AG825, which selectively inhibits the ErbB2 kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Growth Stimulation of Non–Small Cell Lung Cancer Cell Lines by Antibody against Epidermal Growth Factor Receptor Promoting Formation of ErbB2/ErbB3 Heterodimers

Maegawa

Takeuchi

Funakoshi

et al. 2007

Molecular Cancer Research

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Antibodies are the most rapidly expanding class of human therapeutics, including their use in cancer therapy. Monoclonal antibodies (mAb) against epidermal growth factor (EGF) receptor (EGFR) generated for cancer therapy block the binding of ligand to various EGFR-expressing human cancer cell lines and abolish ligand-dependent cell proliferation. In this study, we show that our mAb against EGFRs, designated as B4G7, exhibited a growth-stimulatory effect on various human cancer cell lines including PC-14, a non -small cell lung cancer cell line; although EGF exerted no growth-stimulatory activity toward these cell lines. Tyrosine phosphorylation of EGFRs occurred after treatment of PC-14 cells with B4G7 mAb, and it was completely inhibited by AG1478, a specific inhibitor of EGFR tyrosine kinase. However, this inhibitor did not affect the B4G7-stimulated cell growth, indicating that the growth stimulation by B4G7 mAb seems to be independent of the activation of EGFR tyrosine kinase. Immunoprecipitation with anti-ErbB3 antibody revealed that B4G7, but not EGF, stimulated heterodimerization between ErbB2 and ErbB3. ErbB3 was tyrosine phosphorylated in the presence of B4G7 but not in the presence of EGF. Further, the phosphorylation and B4G7-induced increase in cell growth were inhibited by AG825, a specific inhibitor of ErbB2. These results show that the ErbB2/ErbB3 dimer functions to promote cell growth in B4G7-treated cells. Changes in receptor-receptor interactions between ErbB family members after inhibition of one of its members are of potential importance in optimizing current EGFR family -directed therapies for cancer. (Mol Cancer Res 2007;5(4):393 -401)

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“…Expression of NRG1α and β at the RNA level was described in four human lung cancer lines; only NRG1α protein was detected in lysates and in conditioned medium. 388 An ERBB3-specific antibody, which blocks the NRG-binding sites on ERBB3, reduced NRG-induced ERBB2/ERBB3 activation significantly and transfection of DN ERBB3 abrogated NRG-induced ERBB2 phosphorylation in a dose-dependent manner.…”

Section: Erbb3 In Lung Cancermentioning

confidence: 96%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines

Cited by 52 publications

References 24 publications

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Growth Stimulation of Non–Small Cell Lung Cancer Cell Lines by Antibody against Epidermal Growth Factor Receptor Promoting Formation of ErbB2/ErbB3 Heterodimers

The ERBB3 receptor in cancer and cancer gene therapy

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