Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Role of TGF beta Signaling in skin carcinogenesis

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Transforming growth factor beta (TGFbeta) signaling plays a complex role in cancer development. Loss of TGFbeta type II receptor (TGFbetaRII), and paradoxical overexpression of TGFbeta1 ligand occur frequently in human cancers. In this application, we will further dissect the mechanisms that mediate the complex functions of TGFbeta1 and its primary receptor, TGFbetaRII, in skin carcinogenesis. We are asking the following questions: 1) Does TGFbeta1- induced inflammation contribute to a tumor promotion effect that overrides its own tumor suppressive effect? 2) Does TGFbetaRII loss in tumor epithelia elicit multiple oncogenic events that promote malignant progression? 3) Do cancers harboring both increased TGFbeta1 and TGFbetapRII loss have a poorer prognosis as a result of the cooperation on malignant progression between these two events? To address these questions, we will use our inducible and keratinocyte-specific transgenic/knockout mice which mimic alterations of TGFbeta1 and TGFbetaRII in human cancer. Skin chemical carcinogenesis experiments, which mimic discrete stages of skin cancer development, will be applied to these mouse models. We propose three specific aims: 1. To assess the role of TGFbeta1-induced inflammation in skin carcinogenesis. 2. To assess the effect epithelial TGFbetaRII loss on malignant progression during skin carcinogenesis and analyze pathological and molecular alterations in TGFbetaRII-null tumor epithelia. 3. To assess the pathological and molecular mechanisms of the cooperation between TGFbeta1 overexpression and TGFbetaRII loss in malignant progression. Assessing the effects of TGFbeta1 overexpression and TGFbetaRII loss on carcinogenesis will provide important insights into cancer prognosis and therapeutic strategies in the future. Furthermore, controlled TGFbeta1 transgene induction or TGFbetaRII deletion will greatly enhance our ability to identify direct molecular targets of TGFbeta1 signaling in carcinogenesis, since changes in gene expression can be examined both shortly after TGFbeta1 induction or TGFbetaRII deletion as well as at later time points after sustained TGFbeta1 induction or TGFbetaRII deletion. Identification of these molecular targets will provide important insights into the molecular and cellular mechanisms of TGFbeta signaling in skin carcinogenesis as well as biomarkers for cancer prognosis and targeted therapies in the future.
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