Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells

DPC4/SMAD4 is a candidate tumor suppressor gene with a strikingly high freq uency of gene alterations in pancreatic cancer that suggests a discrete rol e for DPC4 in these tumors. DPC4 tumor-suppressive function has been implic ated to mediate the transforming growth factor-beta (TGF beta)-suppressive pathway; however, in a DPC4-null pancreatic cancer cell line, TGF beta grow th-inhibitory and transcriptional responses were found to be DPC4-independe nt. This was observed within native cells having a natural homozygous delet ion and in clones engineered for stable expression of wild-type DPC4 integr ated into the genome. This observation contrasted with the absolute DPC4 de pendence of TGF beta responses in a breast cancer cell line studied in para llel. This growth-inhibitory response to TGF beta in DPC4-null cells relied on an intact ras effector pathway. These data further suggest a major cate gorization of TGF beta responses into DPC4-dependent and -independent signa ling pathways and specifically suggest that disruption of the TGF beta-inde pendent signal might be a basis of selection for the emergence of DPC4 alte rations during tumorigenesis in the pancreas and other sites. (C) 1999 Wile y-Liss, Inc.