We previously showed that antral gastric tumors develop in gastrin-deficient (Gas(-/-)) mice. Therefore Gas(-/-) mice were studied sequentially over 12 months to identify molecular mechanisms underlying gastric transformation. Fundic atrophy developed by 9 months in Gas-/-mice. Antral mucosal hyperplasia developed coincident with the focal loss of TFF1 and Muc5AC. Microarray analysis of 12 month Gas-tumors revealed an increase in follistatin, an activin/BMP antagonist. We found that elevated follistatin expression Occurred in the proliferative neck zone of hyperplastic antrums, in antral tumors of Gas(-/-) mice. and also in human gastric cancers. Follistatin induced cyclin D1 and the trefoil factors TFF1 and TFF2 in a gastric cancer cell line. We concluded that antral hyperplasia in Gas(-/-) mice involves amplification Of Mucous cell lineages due to follistatin, suggesting its role in the development of antral gastric tumors. (c) 2008 Elsevier Inc. All rights reserved.