The relative role of ErbB1–4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells

Bowers, Geoffrey; Reardon, Dean B.; Hewitt, Timothy E.; Dent, Paul; Mikkelsen, Ross B.; Valerie, Kristoffer; Lammering, Guido; Amir, Cyrus; Schmidt‐Ullrich, Rupert

doi:10.1038/sj.onc.1204255

Cited by 138 publications

(122 citation statements)

References 38 publications

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“…Although Hsp90 inhibition results in the loss of a number of radioresponse associated proteins, because the loss of ErbB2 best correlated with radiosensitization after treatment with 17DMAG or 17AAG (8,9) and because of the putative significance of ErbB signaling in radioresponse (27,(30)(31)(32), we have initially focused on this protein. ErbB2 is a member of the ErbB tyrosine kinase receptor family, which also includes ErbB1 (epidermal growth factor receptor), ErbB3, and ErbB4 (22).…”

Section: Discussionmentioning

confidence: 99%

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

et al. 2005

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The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radiosensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensitivity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient. (Cancer Res 2005; 65(15): 6967-75)

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Section: Discussionmentioning

confidence: 99%

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

et al. 2005

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“…These data represent the most direct demonstration that radiation-induced activation of EGFR species provides a strong cytoprotective signal with increased radioresistance through enhanced proliferation and repair Reardon et al, 1999;Lammering et al, 2001a). From studies on p185neu (ERBB2), the impact of ERBB receptors on cellular radiosensitivity may not be limited to EGFR and its mutants (O'Rourke et al, 1997(O'Rourke et al, , 1998a, but likely depend upon the entire ERBB expression profile of a given tumor cell (Bowers et al, 2001;Lammering et al, 2001a;Contessa et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

EGFRvIII-mediated radioresistance through a strong cytoprotective response

et al. 2003

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“…Although no known ligand has been identified, ErbB2 is the preferred heterodimerization partner for all ErbB family members, and it plays a pivotal role in the ErbB receptor-mediated signaling (Plowman et al, 1993;Sliwkowski et al, 1994;Carraway et al, 1995;Tzahar et al, 1996;Graus-Porta et al, 1997). Recent studies indicate that the status of ErbB2 expression in a given cell is critical in determining the cellular response to growth factors or environmental stimuli (SchmidtUllrich et al, 1999;Spencer et al, 2000;Bowers et al, 2001;Sun et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro

Lin

Leonard

et al. 2003

Oncogene

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Both epidemiological and experimental studies indicate that ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the molecular mechanisms underlying ethanol-mediated tumor promotion remain unknown. Overexpression of ErbB proteins in breast cancer patients is generally associated with poor prognosis. The ErbB proteins are a family of receptor kinases that include four closely related members: epidermal growth factor receptor (EGFR/ErbB1), ErbB2/neu, ErbB3, and ErbB4. Particularly, ErbB2 plays a pivotal role in ErbB-mediated activities. Here we demonstrated that amplification of ErbB2 expression sensitized a specific cellular response to ethanol. Human breast cancer cells or mammary epithelial cells with a high expression of ErbB2 exhibited an enhanced response to ethanol-stimulated cell invasion in vitro. Ethanol also stimulated cell proliferation; however, this stimulation was independent of ErbB2 levels. Ethanol triggered divergent intracellular signaling among cells expressing different ErbB2 levels. In the cells overexpressing ErbB2, ethanol was more effective in the activation of c-Jun NH 2 terminal protein kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK) as well as the induction of reactive oxygen species (ROS) than the cells with normal ErbB2 expression. Blockage of either JNKs or p38 MAPK activation eliminated ethanol-mediated cell invasion. In contrast, the reduction of hydrogen peroxide concentration by catalase exposure had little effect on ethanolinduced cell invasion. These results indicated that ethanolinduced cell invasion was primarily mediated by JNKs and p38 MAPK, whereas the involvement of ROS formation might be minimal. Our study suggests that overexpression of ErbB2 may augment ethanol-elicited signaling and promote ethanol-stimulated tumor metastasis.

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The relative role of ErbB1–4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells

Cited by 138 publications

References 38 publications

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

EGFRvIII-mediated radioresistance through a strong cytoprotective response

Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro

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