P5-02-01: ErbB4 Ectodomain as a Biomarker and a Potential Therapeutic Target for Breast Cancer
Abstract ErbB4 function is controversial in breast cancer and influenced by alternative splicing of the ERBB4 gene. Here we evaluated the cleavable ErbB4 JM-a isoform as a potential drug target and biomarker. To address ErbB4 cleavage in breast cancer tissues in vivo, extracellular and intracellular...
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| Published in: | Cancer research (Chicago, Ill.) Vol. 71; no. 24_Supplement; pp. P5 - P5-02-01 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
15-12-2011
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| Online Access: | Get full text |
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| Summary: | Abstract
ErbB4 function is controversial in breast cancer and influenced by alternative splicing of the ERBB4 gene. Here we evaluated the cleavable ErbB4 JM-a isoform as a potential drug target and biomarker. To address ErbB4 cleavage in breast cancer tissues in vivo, extracellular and intracellular cleavage products of ErbB4 were assessed by ELISA and immunohistochemistry using matched serum and tissue samples from a series of 243 breast cancer patients. Elevated serum ectodomain level (≥40 ng/mL) and nuclear immunoreactivity were present in 21% and 52% of the patients, respectively. An elevated serum ErbB4 ectodomain concentration was not associated with tumor nuclear immunoreactivity, but was significantly associated with the premenopausal status at diagnosis (P = 0.04). Estradiol also enhanced ErbB4 cleavage and ErbB4 cleaving enzyme activity in vitro, supporting a role for estrogen signaling in regulation of ErbB4 cleavage. Selective targeting of the cleavable ErbB4 JM-a in human breast cancer cells with an ErbB4 isoform-specific mAb 1479 inhibited ErbB4 cleavage and reduced tumor formation in a mouse xenograft model. Consistent with blocking of ErbB4 cleavage, mutagenesis studies and the 3.4 Å X-ray crystal structure of a complex of the ErbB4 extracellular region and the 1479 Fab localized the binding site of mAb 1479 on ErbB4 to a region on subdomain IV encompassing JM-a-specific residues. These data demonstrate that ErbB4 is cleaved in a subset of breast cancer patients, and suggest that the mechanisms by which mAb 1479 suppresses breast cancer cell growth involves inhibition of ErbB4 cleavage. Serum ErbB4 ectodomain concentration could be used as a biomarker to monitor the activity of compounds, such as mAb 1479, that target ErbB4 cleavage.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-02-01. |
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| ISSN: | 0008-5472 1538-7445 |
| DOI: | 10.1158/0008-5472.SABCS11-P5-02-01 |