The RNA-binding protein Tristetraprolin (TTP, ZFP36) functions as a tumor suppressor that impairs the development and disables the maintenance of MYC-driven lymphoma. In addition, other human cancers expressed reduced levels of TTP, suggesting that it may function as a tumor suppressor in several malignancies. To identify genes that may be associated with TTP tumor suppressor functions in human cancer, we analyzed The Cancer Genome Atlas (TCGA) breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, and colon adenocarcinoma datasets. These analyses defined a signature of 50 genes differentially regulated between high and low TTP-expressing tumors. Notably, patients with low TTP-expressing breast cancer and lung adenocarcinoma had decreased survival rates and more aggressive tumors with increased necrosis. In addition, analysis across non-TCGA tumor gene expression databases identified a broad spectrum of human cancers having similarities with the TTP-low tumor gene signature, including pancreatic, bladder, and prostate cancer. TTP has documented roles in regulating mRNAs encoding inflammatory proteins, and pathway analysis identified several inflammatory pathways that are altered in tumors with low TTP expression. Surprisingly, the TTP-low tumor gene signature includes a core component of 20 under-expressed CREB target genes, suggesting that the regulation of CREB activity may be related to the tumor suppressor function of TTP. Thus, reduced levels of TTP are a potential biomarker for human cancers with poor outcome, and targeting the CREB pathway may be a therapeutic route for treating aggressive TTP-low tumors.