Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer.
Malignant breast carcinoma cell lines are frequently refractory to transforming growth factor beta (TGF-beta)-mediated cell cycle arrest. To identify molecular mechanisms of TGF-beta resistance, we have conducted a comprehensive structural analysis of the TGF-beta receptor types I (TbetaR-I) and II (TbetaR-II) genes in primary human breast carcinomas and associated axillary lymph node metastases. No evidence for loss of expression (n=14) or structural alterations of the TbetaR-II gene (n=30) were identified. However, 2 of 31 primary carcinomas and 5 of 12 lymph node metastases carried a C to A transversion mutation resulting in a serine to tyrosine substitution at codon 387 (S387Y) of the TbetaR-I receptor gene. This TbetaR-I mutant has a diminished ability to mediate TGF-beta-dependent effects on gene expression as compared with wild-type TbetaR-I. S387Y is the first reported mutation in the TbetaR-I gene in human cancer that was primarily associated with lymph node metastases in the present series.
Chen
T
T
Department of Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Carter
D
D
Garrigue-Antar
L
L
Reiss
M
M
D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*
D018125:Receptors, Transforming Growth Factor beta