Mitogenic activity of neu differentiation factor/heregulin mimics that of epidermal growth factor and insulin-like growth factor-I in human mammary epithelial cells.
Recently, a family of growth factors has been described that activates erbB-2 receptors. These factors, known as the neu differentiation factors (NDF) or heregulins (HRG), induce tyrosine phosphorylation of erbB-2 receptors as a result of their direct interaction with either erbB-3 or erbB-4 receptors. Although it is known that expression of erbB-2 receptors has relevance in human breast cancer progression, how erbB-2, -3 and -4 receptors regulate mammary epithelial cell proliferation is not known. Therefore, experiments were carried out to study the mitogenic activity of NDF/HRG on the human mammary epithelial cell line MCF-10A which can be cultured continuously under serum-free conditions. MCF-10A cells, like primary cultures of normal human mammary epithelial cells, express an absolute requirement for exogenous epidermal growth factor (EGF) and insulinlike growth factor I (IGF-I) for growth. The results of these experiments indicate that NDF/HRG can induce tyrosine phosphorylation of p185erbB-2 in MCF-10A cells and is mitogenic for these cells. This is consistent with the coexpression of erbB-2 and erbB-3 mRNA that we have observed in MCF-10A cells. In addition, we found that NDF/HRG can substitute for either EGF or IGF-I to stimulate proliferation of these cells. The ability to substitute for both EGF and IGF-I is a unique property of NDF/HRG and is not shared by other members of the EGF or IGF family of growth factors, nor by other factors that we have studied. A striking isoform specificity was also observed which indicated that the beta-isoforms of NDF/HRG were greater than ten times more mitogenic than the alpha-isoforms. We also examined the mitogenic activity of NDF/HRG on MCF-10A cells that overexpress the erbB-2 receptor as a result of infection with a retroviral vector containing the human c-erbB-2 gene (MCF-10AerbB-2 cells). These studies indicated that MCF-10AerbB-2 cells have increased sensitivity to the mitogenic effects of NDF/HRG and that these cells are responsive to the alpha-isoforms of NDF/HRG at physiological concentrations. Thus, NDF/HRG is a dual specificity growth factor for human mammary epithelial cells, and the responsiveness of the cells to NDF/HRG is influenced by the level of expression of erbB-2 receptors.
Ram
T G
TG
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor 48109-0582, USA.
Kokeny
K E
KE
Dilts
C A
CA
Ethier
S P
SP
D001483:Base Sequence; D001940:Breast / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology*; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
D004815:Epidermal Growth Factor; D006023:Glycoproteins; D007334:Insulin-Like Growth Factor I; D008934:Mitogens; D015335:Molecular Probes; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases