title: Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells.
abstract: The function of the epidermal growth factor receptor (EGFR) family member HER4 remains unclear because its activating ligand, heregulin, results in either proliferation or differentiation. This variable response may stem from the range of signals generated by HER4 homodimers versus heterodimeric complexes with other EGFR family members. The ratio of homo- and heterodimeric complexes may be influenced both by a cell's EGFR family member expression profile and by the ligand or even ligand isoform used. To define the role of HER4 in mediating antiproliferative and differentiation responses, human breast cancer cell lines were screened for responses to heregulin. Only cells that expressed HER4 exhibited heregulin-dependent antiproliferative responses. In-depth studies of one line, SUM44, demonstrated that the antiproliferative and differentiation responses correlated with HER4 activation and were abolished by stable expression of a kinase-inactive HER4. HB-EGF, a HER4-specific ligand in this EGFR-negative cell line, also induced an antiproliferative response. Moreover, introduction and stable expression of HER4 in HER4-negative SUM102 cells resulted in the acquisition of a heregulin-dependent antiproliferative response, associated with increases in markers of differentiation. The role of HER2 in these heregulin-dependent responses was examined through elimination of cell surface HER2 signaling by stable expression of a single-chain anti-HER2 antibody that sequestered HER2 in the endoplasmic reticulum. In the cell lines with either endogenously (SUM44) or exogenously (SUM102) expressed HER4, elimination of HER2 did not alter HER4-dependent decreases in cell growth. These results suggest that HER4 is both necessary and sufficient to trigger an antiproliferative response in human breast cancer cells.
authors.affiliation: Department of Radiation Oncology, University of North Carolina, Chapel Hill, North Carolina 27599-7512, USA. sartor@radonc.unc.edu
authors.forename: C I
authors.initials: CI
authors.lastname: Sartor
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: E
authors.initials: E
authors.lastname: Kozlowska
authors.forename: K
authors.initials: K
authors.lastname: Guttridge
authors.forename: E
authors.initials: E
authors.lastname: Kawata
authors.forename: L
authors.initials: L
authors.lastname: Caskey
authors.forename: J
authors.initials: J
authors.lastname: Harrelson
authors.forename: N
authors.initials: N
authors.lastname: Hynes
authors.forename: S
authors.initials: S
authors.lastname: Ethier
authors.forename: B
authors.initials: B
authors.lastname: Calvo
authors.forename: H S
authors.initials: HS
authors.lastname: Earp
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D048429:Cell Size; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D020890:Neuregulin-1; D019000:Phosphotyrosine; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C587883:HBEGF protein, human; C087230:heregulin beta1; C587689:ERBB4 protein, human