Transforming growth factor-alpha is a member of the epidermal growth GDC-0449 factor family of cytokines, which acts in autocrine and paracrine fashions by binding to the EGF receptor to regulate cell proliferation, differentiation, transformation, and migration. Overexpression of TGF�� has been reported in transformed cells of many cancer types, including the acinar cells and ductal epithelium in human pancreatic cancer. Transgenic mice expressing TGF�� transgene under the control of zinc-inducible metallothionein promoter/enhancer or elastase promoter exhibited progressive pancreatic fibrosis, loss of acinar cell mass, and development of extensive tubular complexes, termed pseudoductular metaplasia. SMAD4, originally isolated from human chromosome 18q21.1, is a key intracellular mediator of transcriptional responses to TGF-��. TGF-�� plays a complicated, biphasic stage-specific role in tumorigenesis by serving as a tumor-suppressor during early initiation, and yet promoting tumor progression in late stages. As a central effector of the TGF-�� pathway, SMAD4 is believed to be a tumor-suppressor gene as evidenced by being biallelically inactivated in more than 50% of pancreatic carcinomas. Smad4 deficiency can lead to rapid progression of pancreatic tumors in the context of activated KrasG12D; however, Smad4 deficiency alone is incapable of initiating pancreatic tumorigenesis and dispensable for normal pancreas development. In addition to its importance in tumorigenesis, TGF-�� signaling has long been recognized to induce extracellular matrix synthesis and tissue fibrosis. While fibrotic disease represents a large group of disorders for which there is no effective therapy, the precise contribution of TGF-�� or Smad4 to fibrotic disease is still unclear. In the case of MG132 chronic pancreatitis, progressive fibrosis and destruction of the gland can result in exocrine and endocrine insufficiency. It has been previously shown that loss of TGF-�� signaling in fibroblasts results in increased TGF��, therefore we set out to examine the possible synergetic effects of Smad4 loss and TGF�� overexpression in vivo. PanIN lesions, which were rarely detected in the MT-TGF�� mice, were a more common occurrence in the STP mice. These results demonstrated that although Smad4 inactivation alone was not sufficient to induce phenotypic changes, it could accerbate the pathological changes initiated by the overexpression of TGF��. Overall, the STP mice displayed histologic presentations reminiscent to those of human chronic pancreatitis transitioning to early tumorigenesis. This was confirmed by the upregulated expression of desmoplasia-associated Col1A1 and chronic pancreatitis-related Muc6 detected in the STP mice, indicating that STP mice may be a suitable animal model for studying the transition of chronic pancreatitis to pancreatic cancer. The combination of TGF�� overexpression and Smad4 deletion in the pancreas of the STP mice presented a number of histologic similarities to human chronic pancreatitis, including increased fibrosis and development of PanIN-1& -2 lesions. Therefore, we further assessed the expression of molecular markers that are associated with chronic pancreatitis or desmoplastic reaction. Given that mucin genes are highly conserved between human and mice and that MUC6 has been reported aberrantly expressed in human chronic pancreatitis, we sought to analyze Muc6 expression levels in the STP and MT-TGF�� mice. Intriguingly, IHC analysis showed enhanced expression of Muc6 in the lumen of the PanIN lesions in the STP mice when compared to the MT-TGF�� mice. PDAC is the fourth leading cause of cancer death in the United States with a five-year survival as low as 6%.