Esophageal cancer represents the 5th most frequent cancer in males worldwide. Given thepoor survival rate, advanced stage of the disease at diagnosis and the increasing frequency ofthe disease it is increasingly important to understand the molecular mechanisms of initiation ofthese tumors as well as the genes involved in their metastasis. My research will focus on p120-catenin (p120ctn) and its ability to modulate tumorigenesis as well as cell migration and invasionin vitro and in vivo. P120ctn defines a subfamily of catenin proteins related to beta-catenin thatalso bind to E-cadherin and stabilizes E-cadherin at adherens junctions. As a result, expressionof E-cadherin and p120ctn appear to be coordinately regulated in many cell lines and it isspeculated that this may be another mechanism by which E-cadherin expression may be lostand lead to EMT. Functionally, we have demonstrated that successful genetic knockdown ofp120ctn results in loss of the integrity of the adherens junctions with augmentation of tumor cellmigration and invasion. This has been pursued as well in a genetically engineered mouse modelthrough tissue specific ablation of p120ctn, resulting in inflammation and cancer in theesophagus. Therefore, we hypothesize that p120ctn regulates tumor cell migration andinvasion by its ability to modulate effectors such as cdc42/rho/rac, and that p120ctn has aparallel and distinct role in tumorigenesis from that of other oncogenes and tumor suppressors.This hypothesis will be pursued by the following interrelated Specific Aims:
Aim 1 : Identifythe pathways regulated by p120ctn involved in cellular transformation Aim 1a: Understand thefunctional role(s) of p120ctn in tumor initiation using immortalized esophageal epithelial cells(keratinocytes).
Aim 1 b: Determine the functional consequences of p120ctn loss in primaryesophageal keratinocytes Aim2: Determine the functional interaction between p120ctn andEGFR overexpression in esophageal tumor initiation.
Aim 3 : Determine the functional role(s) ofp120ctn in tumor progression in mouse models of esophageal cancer.
Over 14,000 new cases of esophageal cancer were diagnosed in the United States last year and more than 90% of those diagnosed will die of their disease, primarily from metastatic lesions. The proposed studies will provide novel insights into the biological roles of p120ctn in the development and progression of esophageal cancer. Ultimately, these studies may translate into new diagnostic and therapeutic modalities for this deadly disease.
