1. ¹Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Department of Surgery, Medicine, Lombardi Cancer Center, Georgetown University, Washington, DC, USA
2. ²Genetics of Development and Disease Branch, NIDDK, NIH, Bethesda, MD, USA
3. ³Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Surgery, Washington, DC, USA
5. ⁵Department of Veterans Affairs, Washington, DC, USA
6. ⁶Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA

Correspondence: L Mishra and B Mishra, Laboratory of Cancer Genetics, Digestive Diseases, and Developmental Molecular Biology, Georgetown University, Medical/Dental Building NW 210-212, 3900 Reservoir Rd, NW, Washington, DC 20007, USA. E-mails: lopamishra@yahoo.com; bm72@georgetown.edu; EP Reddy, Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA 19140, USA

⁶These authors contributed equally to the work.

Received 15 June 2005; Revised 13 September 2005; Accepted 14 September 2005; Published online 14 November 2005.

Abstract

Inactivation of the transforming growth factor- (TGF-) pathway occurs often in malignancies of the gastrointestinal (GI) system. However, only a fraction of sporadic GI tumors exhibit inactivating mutations in early stages of cancer formation, suggesting that other mechanisms play a critical role in the inactivation of this pathway. Here, we show a wide range of GI tumors, including those of the stomach, liver and colon in elf^+/- and elf^+/-/Smad4^+/- mutant mice. We found that embryonic liver fodrin (ELF), a -Spectrin originally identified in endodermal stem/progenitor cells committed to foregut lineage, possesses potent antioncogenic activity and is frequently inactivated in GI cancers. Specifically, E-cadherin accumulation at cell–cell contacts and E-cadherin--catenin-dependent epithelial cell–cell adhesion is disrupted in elf^+/-/Smad4^+/- mutant gastric epithelial cells, and could be rescued by ectopic expression of full-length elf, but not Smad3 or Smad4. Subcellular fractionation revealed that E-cadherin is expressed mainly at the cell membrane after TGF- stimulation. In contrast, elf^+/-/Smad4^+/- mutant tissues showed abnormal distribution of E-cadherin that could be rescued by overexpression of ELF but not Smad3 or Smad4. Our results identify a group of common lethal malignancies in which inactivation of TGF- signaling, which is essential for tumor suppression, is disrupted by inactivation of the ELF adaptor protein.