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Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer
T Chen1, D Carter, L Garrigue-Antar
1Department of Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Abstract:
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.
Insights
Transforming growth factor beta (TGF-β) resistance in breast cancer involves mutations in the TGF-β receptor type I (TβR-I) gene. A specific TβR-I mutation (S387Y) was identified, particularly in lymph node metastases, impacting TGF-β signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant breast carcinoma cell lines often resist transforming growth factor beta (TGF-β)-induced cell cycle arrest.
- Understanding the molecular basis of TGF-β resistance is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the structural alterations in TGF-β receptor types I (TβR-I) and II (TβR-II) genes in human breast carcinomas and metastases.
- To identify molecular mechanisms underlying TGF-β resistance in breast cancer.
Main Methods:
- Comprehensive structural analysis of TβR-I and TβR-II genes in primary human breast carcinomas and axillary lymph node metastases.
- Mutation screening and assessment of gene expression.
Main Results:
- No structural alterations or loss of expression were found in the TβR-II gene.
- A specific mutation, C to A transversion at codon 387 (S387Y), was identified in the TβR-I gene in 2 of 31 primary carcinomas and 5 of 12 lymph node metastases.
- The TβR-I S387Y mutant exhibited reduced ability to mediate TGF-β-dependent gene expression compared to wild-type.
Conclusions:
- The TβR-I S387Y mutation is the first reported mutation in this gene associated with human cancer.
- This mutation appears primarily linked to lymph node metastases in breast cancer.
- The identified TβR-I mutation contributes to TGF-β resistance in breast carcinoma.