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Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells
J L Dai1, M Schutte, R K Bansal
1Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Molecular Carcinogenesis
|September 16, 1999
Summary
DPC4/SMAD4 alterations are frequent in pancreatic cancer. TGFbeta responses can be DPC4-independent, relying on the ras pathway, suggesting a new categorization of TGFbeta signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- DPC4/SMAD4 is a candidate tumor suppressor gene frequently altered in pancreatic cancer.
- Its tumor-suppressive function is linked to the transforming growth factor-beta (TGFbeta) pathway.
Purpose of the Study:
- To investigate the role of DPC4 in TGFbeta signaling in pancreatic cancer.
- To determine if TGFbeta responses are DPC4-dependent or independent in pancreatic cancer cells.
Main Methods:
- Utilized DPC4-null pancreatic cancer cell lines with natural homozygous deletion.
- Engineered clones for stable expression of wild-type DPC4.
- Compared TGFbeta responses in DPC4-null and DPC4-expressing cells.
- Analyzed TGFbeta responses in parallel using a breast cancer cell line.
Main Results:
- TGFbeta growth-inhibitory and transcriptional responses were DPC4-independent in DPC4-null pancreatic cancer cells.
- This independence was maintained even after reintroducing DPC4.
- In contrast, TGFbeta responses were DPC4-dependent in a parallel breast cancer cell line.
- TGFbeta-induced growth inhibition in DPC4-null cells depended on an intact ras effector pathway.
Conclusions:
- TGFbeta responses can be categorized into DPC4-dependent and DPC4-independent signaling pathways.
- Disruption of the TGFbeta-independent pathway may drive DPC4 alterations during pancreatic tumorigenesis.