Accession Number : ADA456265


Title :   p38 Mitogen-Activated Protein Kinase in Metastasis Associated with Transforming Growth Factor Beta


Descriptive Note : Final rept. 15 May 2002-14 May 2006


Corporate Author : HEALTH RESEARCH INC BUFFALO NY


Personal Author(s) : Bakin, Andrei


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a456265.pdf


Report Date : Jun 2006


Pagination or Media Count : 103


Abstract : Malignant breast cancers express high levels of transforming growth factor beta1 (TGF-beta1). TGF-beta1 is a potent tumor suppressor, but, paradoxically, it has been implicated in metastasis by stimulating epithelial to mesenchymal transition (EMT), cell migration, invasion, and changes in tumor microenvironment. The goal is to develop therapies that selectively suppress oncogenic function of TGF-beta1. The premise to this study was our original observation that inhibition of p38 mitogenactivated protein kinase (p38MAPK) selectively blocked TGFbeta-induced EMT and cell migration but not growth-inhibitory function of TGF-beta1. This suggested that the p38MAPK pathway is critical for oncogenic function of TGF-beta1. The purpose of this proposal was to define in vitro and in vivo the role of the p38MAPK pathway in oncogenic function of TGF-beta1 in metastasis. We provide evidence that autocrine TGF-beta1-MAPK signaling in breast cancer cells contributes to tumor cell migration, invasion, and, importantly, to tumor angiogenesis. The mechanisms involve at least two distinct pathways mediated by MMP9/gelatinase-B and p38MAPK. p38MAPK is required for cell motility and tumor angiogenesis but it is dispensable for regulation of MMP9. MEK-ERK and TAK1 contribute to MMP9 expression. Thus, MEK-ERK, TAK1, and p38MAPK represent potential targets for anticancer/metastastic therapy associated with oncogenic TGF-beta1.


Descriptors :   *METASTASIS , *BREAST CANCER , PROTEINS , NEOPLASMS , IN VITRO ANALYSIS , THERAPY , MIGRATION , ANGIOGENESIS , IN VIVO ANALYSIS , CELLS(BIOLOGY) , POTENCY , SUPPRESSORS , GROWTH(PHYSIOLOGY) , PHOSPHORUS TRANSFERASES


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE