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Proteolytic processing of ErbB4 in breast cancer
Maija Hollmén1, Ping Liu, Kari Kurppa
1Medicity Research Laboratories, Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
Plos One
|July 5, 2012
Summary
Elevated ErbB4 ectodomain in serum indicates enhanced ErbB4 processing in breast cancer. This cleavage, stimulated by estradiol, can be blocked by mAb 1479, suppressing tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- ErbB4 receptor tyrosine kinase signaling involves proteolytic cleavage.
- Proteolysis-dependent ErbB4 signaling is implicated in breast cancer progression.
- Direct in vivo assessment of ErbB4 processing in breast cancer was lacking.
Purpose of the Study:
- To quantify cleaved ErbB4 ectodomain in breast cancer patient serum.
- To investigate the relationship between serum ErbB4 ectodomain and tumor characteristics.
- To explore the role of estradiol in ErbB4 cleavage and to evaluate therapeutic targeting of ErbB4 cleavage.
Main Methods:
- Developed an ELISA to measure serum ErbB4 ectodomain levels.
- Analyzed serum samples from 238 breast cancer patients and 30 healthy controls.
- Determined ErbB4 crystal structure, assessed estradiol's effect on cleavage in vitro, and evaluated mAb 1479 efficacy in vivo.
Main Results:
- 21% of breast cancer patients showed elevated serum ErbB4 ectodomain compared to 0% of controls (P = 0.002).
- Elevated serum ErbB4 ectodomain did not correlate with nuclear ErbB4, but was associated with premenopausal status (P = 0.04).
- Estradiol enhanced ErbB4 cleavage in vitro; mAb 1479 blocked ErbB4 cleavage in vivo and suppressed tumor xenograft growth.
Conclusions:
- ErbB4 processing is enhanced in breast cancer.
- Estradiol stimulates ErbB4 cleavage, suggesting a hormonal influence.
- Targeting ErbB4 cleavage with mAb 1479 represents a potential therapeutic strategy for breast cancer.
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