Transforming growth factor-β responsiveness in DPC4/SMAD4-Null cancer cells

DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high frequency of gene alterations in pancreatic cancer that suggests a discrete role for DPC4 in these tumors. DPC4 tumor-suppressive function has been implicated to mediate the transforming growth factor-β (TGFβ)-suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGFβ growth- inhibitory and transcriptional responses were found to be DPC4-independent. This was observed within native cells having a natural homozygous deletion and in clones engineered for stable expression of wild-type DPC4 integrated into the genome. This observation contrasted with the absolute DPC4 dependence of TGFβ responses in a breast cancer cell line studied in parallel. This growth-inhibitory response to TGFβ in DPC4-null cells relied on an intact ras effector pathway. These data further suggest a major categorization of TGFβ responses into DPC4-dependent and -independent signaling pathways and specifically suggest that disruption of the TGFβ- independent signal might be a basis of selection for the emergence of DPC4 alterations during tumorigenesis in the pancreas and other sites.