[Show abstract][Hide abstract] ABSTRACT: In many studies, ErbB4 expression in breast tumor samples correlates with a favorable patient prognosis. Similarly, ErbB4 signaling is coupled to cellular differentiation and growth arrest in a variety of model systems. However, in some studies, ErbB4 expression in breast tumor samples correlates with poor outcome. Likewise, studies using some human mammary tumor cell lines suggest that ErbB4 is coupled to malignant phenotypes. Thus, the roles that ErbB4 plays in human breast cancer are still poorly defined. Here we demonstrate that a constitutively active ErbB4 mutant (ErbB4-Q646C) inhibits colony formation on plastic by two human mammary tumor cell lines (SKBR3 and MCF7) and by the MCF10A immortalized human mammary cell line, but does not inhibit colony formation by the MDA-MB-453 and T47D human mammary tumor cell lines. ErbB4 kinase activity is necessary for ErbB4 function and phosphorylation of ErbB4 Tyr1056 is necessary and appears to be sufficient for ErbB4 function. The inhibition of colony formation by MCF10A cells is accompanied by growth arrest but not cell death. These data suggest that ErbB4 behaves as a mammary tumor suppressor and that loss of ErbB4 coupling to growth arrest may be an important event in mammary tumorigenesis.
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 02/2006; 16(4):179-93. · 1.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ErbB4 (HER4) is a member of the ErbB family of receptor tyrosine kinases, a family that also includes the Epidermal Growth Factor Receptor (EGFR/ErbB1/HER1), Neu/ErbB2/HER2, and ErbB3/HER3. Several groups have hypothesized that signal transduction by the ErbB4 receptor tyrosine kinase is coupled to differentiation, growth arrest, and tumor suppression in mammary and prostate epithelial cells. In this report we demonstrate that a constitutively active ErbB4 mutant inhibits the formation of drug-resistant colonies by the DU-145 and PC-3 human prostate tumor cell lines. This is consistent with our hypothesis that ErbB4 signaling is growth inhibitory and may be coupled to tumor suppression in prostate cells.
Cancer Letters 04/2003; 192(1):67-74. · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ErbB4 is a member of the epidermal growth factor receptor(EGFR) family of tyrosine kinases, which includes EGFR/ErbB1, ErbB2/HER2/Neu, and ErbB3/HER3. These receptors play important roles both in normal development and in neoplasia. For example, deregulated signaling by ErbB1 and ErbB2 is observed in many human malignancies. In contrast, the roles that ErbB4 plays in tumorigenesis and normal biological processes have not been clearly defined. To identify the biological responses that are coupled to ErbB4, we have constructed three constitutively active ErbB4 mutants. Unlike a constitutively active ErbB2 mutant, the ErbB4 mutants are not coupled to increased cell proliferation, loss of contact inhibition, or anchorage independence in a rodent fibroblast cell line. This suggests that ErbB2 and ErbB4 may play distinct roles in tumorigenesis in vivo.
Cell growth & differentiation: the molecular biology journal of the American Association for Cancer Research 07/2002; 13(6):247-56.