1. ¹Department of Structural and Cellular Biology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, USA
2. ²Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, USA
3. ³Louisiana State University Health Sciences Center, Gene Therapy Program, The Morphology and Imaging Core Laboratory, New Orleans, LA, USA

Correspondence: Dr FE Jones, Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. E-mail: fjones@tulane.edu

Received 10 December 2004; Revised 25 April 2006; Accepted 29 May 2006; Published online 10 July 2006.

Abstract

In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression. In addition, ERBB4 functions as a proapoptotic protein, suppressing the growth of malignant cells. We hypothesize that these ERBB4 activities can be marshaled to suppress the growth of breast tumors. To this end, we have created an ERBB4 allele harboring an activating transmembrane mutation (ERBB4-CA) by substituting isoleucine 658 for glutamic acid. This base substitution forms a valine-glutamic acid-glycine activation domain first identified in oncogenic ERBB2/HER2/Neu. Ectopic expression of ERBB4-CA in HEK293T cells resulted in a fivefold increase in receptor tyrosine phosphorylation. Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the -casein promoter. Activated ERBB4 has been demonstrated to induce cell killing of breast tumor cells. Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested. Untransformed cell lines were resistant to both ERBB4 and ERBB4-CA-mediated apoptosis underscoring the potential utility of active ERBB4 signaling for the therapeutic intervention of human cancer.