Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake.

Hurwitz, Esther; Stancovski, Ilana; Sela, Michael; Yarden, Yosef

doi:10.1073/pnas.92.8.3353

Cited by 135 publications

(109 citation statements)

References 28 publications

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“…The laminin-induced removal of pl85HER2 from the cell surface may result in decreased growth of those tumour cells that overexpress this receptor. Consistent with the hypothesis that the oncogenic potential of p185HER2 is restricted to the membrane form, antibody-mediated internalisation of this receptor was associated with inhibition of tumour growth (Hurwitz et al, 1995). Moreover, a cytoplasmic localisation of c-erbB-2 in breast carcinomas has been linked to better prognosis compared with tumours that showed cell membrane localisation of this receptor (Zschiesche et al, 1994).…”

Section: Discussionsupporting

confidence: 65%

“…Amplification of the c-erbB-2 gene and overexpression of its product induce cell transformation (Di Fiore et al, 1987) and have been associated with poor prognosis in different tumours of epithelial origin (Rilke et al, 1991;Berchunck et al, 1990;Kern et al, 1990;Gullick, 1990;Slamon et al, 1989). Monoclonal antibodies (MAbs) directed to pl85HER2 (Hurwitz et al, 1995;Stancovski et al, 1991;Tagliabue et al, 1991;Hudziak et al, 1989;McKenzie et al, 1989), as well as different candidate ligands of the p185HER2 receptor (Samanta et al, 1994;Huang et al, 1992;Wen et al, 1992;Holmes et al, 1992;Peles et al, 1992;Dobashi et al, 1991, Tarakhovsky et al, 1991Lupu et al, 1990;Yarden et al, 1989) and oestrogen (Matsuda et al, 1993), have been shown either to stimulate or to inhibit cell growth. c-erbB-2 can also be activated by interaction with other activated members of the EGF receptor family.…”

mentioning

confidence: 99%

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Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells

Tagliabue

Ardini²,

Pellegrini³

et al. 1996

Br J Cancer

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Summary The interaction between laminin and the oncoprotein encoded by the c-erbB-2 oncogene was studied in vitro and in vivo in human breast carcinomas. In vitro analysis of breast carcinoma cell lines overexpressing p185HER2 revealed that laminin, but not fibronectin, induced tyrosine phosphorylation and down-modulation of oncoprotein membrane expression. Laminin also specifically inhibited growth of pl85HER2_positive cell lines. No direct binding between the recombinant extracellular domain of pl85HER2 and laminin was found. Induction of oncoprotein down-modulation by anti-integrin antibodies and coprecipitation of the oncoprotein with the fl4 integrin subunit indicate that the interaction between p185HER2 and laminin occurs through integrin molecules. The relevance of this in vitro observation was verified in vivo by analysing the prognostic value of p185HER2 overexpression as a function of laminin production on archival paraffin-embedded sections of 887 primary breast tumours. The results revealed an association between pl85HER2 overexpression and unfavourable prognosis in tumours negative for laminin production, whereas in laminin-producing tumours, the oncoprotein overexpression was not associated with tumour aggressiveness.

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells

Tagliabue

Ardini²,

Pellegrini³

et al. 1996

Br J Cancer

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“…However, all three e ects are strictly dependent on antibody bivalency (Hurwitz et al, 1995 and data not shown), implying their association with ErbB-2 homodimers. (iii) All mAbs that are directed to the most antigenic site of ErbB-2 (Class II mAbs) are able to inhibit crosstalk with EGF-and NDF-receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence indicate a correlation between tumor-inhibitory activity of mAbs and their ability to accelerate ErbB-2 uptake and down-regulation (Hurwitz et al, 1995;Tagliabue et al, 1991). To test the applicability of such a correlation to the new inhibitory mAbs, we studied I-mAb was used as a measure for the degree of antigenic overlap.…”

Section: Classi®cation Of Anti-erbb-2 Monoclonal Antibodiesmentioning

confidence: 99%

“…Accelerated down-regulation of the receptor has been suggested to mediate antibody inhibition of cell transformation (Hudziak et al, 1989;van Leeuwen et al, 1990). However, the ability of mAbs to induce receptor internalization showed only partial correlation with anti-tumorigenic activity (Harwerth et al, 1992;Hurwitz et al, 1995). An obstacle in the understanding of mAb-mediated e ects is the possibility that ErbB-2 has a direct ligand, that has not yet been completely characterized (Dougall et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors

et al. 1997

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ErbB-2 is an orphan receptor that belongs to a family of tyrosine kinase receptors for either epidermal growth factor (EGF) or Neu di erentiation factor (NDF/ neuregulin). Because overexpression of the erbB-2 proto-oncogene is frequently associated with an aggressive clinical course of certain human adenocarcinomas, the encoded protein is an attractive target for immunotherapy. Indeed, certain monoclonal antibodies (mAbs) to ErbB-2 e ectively inhibit tumor growth in animal models and in clinical trials, but the underlying mechanism is incompletely understood. To study this question, we generated a large battery of mAbs to ErbB-2, that were classi®ed epitopically. Whereas most antibodies stimulated tyrosine phosphorylation of ErbB-2, their anti-tumor e ect correlated with its accelerated endocytic degradation. One group of tumor-inhibitory mAbs (Class II mAbs) was elicited by the most antigenic site of ErbB-2, and inhibited in trans binding of NDF and EGF to their direct receptors. The inhibitory e ect was due to acceleration of ligand dissociation, and it resulted in the reduction of the ability of ErbB-2 to transactivate the mitogenic signals of NDF and EGF. These results identify two potential mechanisms of antibody-induced therapy: acceleration of ErbB-2 endocytosis by homodimerization and blocking of heterodimerization between ErbB-2 and growth factor receptors.

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ERbB-2 expression is rate-limiting for epidermal growth factor-mediated stimulation of ovarian cancer cell proliferation

et al. 2000

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Over‐expression of the ErbB‐2 proto‐oncogene frequently coincides with an aggressive clinical course of certain human adenocarcinomas. The ErbB‐2 receptor is a member of the ErbB family of growth factor receptors, and within this complex signaling network, ErbB‐2‐containing heterodimers are preferentially formed. To assess whether ErbB‐2 is a critical component in epidermal growth factor (EGF)–mediated stimulation of tumor cell proliferation, we used as a model SK‐OV‐3 ovarian cancer cells, which over‐express EGF receptor (EGFR) and ErbB‐2 receptors. In these cells, we reduced ErbB‐2 mRNA and protein expression by transfection with ErbB‐2‐targeted hammerhead ribozymes and generated cell lines expressing different levels of ErbB‐2. In SK‐OV‐3 cells, ErbB‐2 expression conferred a growth advantage and soft agar experiments revealed that ErbB‐2 was rate‐limiting for anchorage‐independent growth. The induction of colony formation by EGF was completely abrogated in ErbB‐2‐depleted cells, despite unchanged expression levels and tyrosine phosphorylation of the EGFR. The duration of EGF‐mediated c‐Fos mRNA up‐regulation was decreased in parallel with loss of ErbB‐2 expression. Furthermore, the rate of spontaneous apoptosis was increased in ErbB‐2‐depleted cells. Our results demonstrate that in human ovarian cancer cells the EGFR–ErbB‐2 heterodimer, and not the EGFR homodimer, can be rate‐limiting for EGF‐mediated proliferation, thus suggesting that the oncogenic activity of ErbB‐2 in human tumors is due in part to its ability to increase the growth response to stroma‐derived EGF‐like growth factors. Int. J. Cancer 86:644–651, 2000. © 2000 Wiley‐Liss, Inc.

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Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake.

Abstract: ABSTRACT

Cited by 135 publications

References 28 publications

Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells

Laminin activates the p185HER2 oncoprotein and mediates growth inhibition of breast carcinoma cells

A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors

ERbB-2 expression is rate-limiting for epidermal growth factor-mediated stimulation of ovarian cancer cell proliferation

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