Malignant breast carcinoma cell lines are frequently refractory to transforming growth factor β (TGF-β)-mediated cell cycle arrest. To identify molecular mechanisms of TGF-β resistance, we have conducted a comprehensive structural analysis of the TGF-β receptor types I (TβR-I) and II (TβR-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 TβR-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 TβR-I receptor gene. This TβR-I mutant has a diminished ability to mediate TGF-β-dependent effects on gene expression as compared with wild-type TβR-I. S387Y is the first reported mutation in the TβR-I gene in human cancer that was primarily associated with lymph node metastases in the present series.
Supported in part by USPHS Award CA41556 from the National Cancer Institute and Breast Cancer Research Program Grant DAMD17-96-1-6024 from the United States Department of Defense.