Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells.
The development of acquired resistance to antihormonal agents in breast cancer is a major therapeutic problem. We have developed a tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line to investigate the mechanisms behind this condition. Both epidermal growth factor receptor (EGFR) and c-erbB2 mRNA and protein expression were increased in TAM-R compared with wild-type MCF-7 cells, whereas comparable levels of c-erbB3 mRNA and protein were expressed in both cell lines. Under basal conditions, phosphorylated EGFR/c-erbB2, EGFR/c-erbB3 but not c-erbB2/c-erbB3 receptor heterodimers were detected in TAM-R cells in association with increased levels of phosphorylated extracellular-signal regulated kinase 1/2 (ERK1/2). Both cell lines were capable of generating a range of EGFR-specific ligands and increased expression of transforming growth factor alpha was observed in TAM-R cells. Treatment of TAM-R cells with ZD1839 (Iressa) or trastuzumab (Herceptin) blocked c-erbB receptor heterodimer formation and phosphorylation, reduced ERK1/2 activity, and strongly inhibited cell growth. The MAPK kinase inhibitor PD098059 specifically reduced phosphorylated ERK1/2 levels and inhibited TAM-R growth. All three agents abolished ERK1/2 activity in wild-type cells but caused only small reductions in cell proliferation. These results demonstrate that TAM-R MCF-7 cell growth is mediated by the autocrine release and action of an EGFR-specific ligand inducing preferential EGFR/c-erbB2 dimerization and downstream activation of the ERK pathway.
Knowlden
Janice M
JM
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, United Kingdom.
Hutcheson
Iain R
IR
Jones
Helen E
HE
Madden
Tracieann
T
Gee
Julia M W
JM
Harper
Maureen E
ME
Barrow
Denise
D
Wakeling
Alan E
AE
Nicholson
Robert I
RI
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D000077156:Gefitinib; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000235:genetics; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005419:Flavonoids; D000077156:Gefitinib; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D011799:Quinazolines; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D016211:Transforming Growth Factor alpha; D000068878:Trastuzumab; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one