STAT3 signal transduction in human malignancy

Inappropriate activation of transcription factors is a common event in cancer. The transcription factor STAT3 contributes to a malignant phenotype by regulating genes involved in cellular proliferation, survival, differentiation, angiogenesis, and invasion, although the identity of these genes remains unknown.; In this dissertation I have addressed the role that the oncogenic transcription factor STAT3 plays in human tumors by analyzing STAT3 target genes. I created a system that allowed for the specific activation of STAT3, and employed this system to identify a comprehensive list of over 100 direct transcriptional targets of STAT3. In addition to characterizing several individual target genes, I analyzed the expression of these genes as a whole in human tumor expression datasets. I thereby identified a cohort of genes which are highly coexpressed with one another in several independent tumor types. Using immunohistochemical staining of tumors with a phospho-STAT3-specific antibody, I showed that these genes are correlated with STAT3 activation in breast and prostate tumors. Furthermore, their expression requires STAT3 in a human breast cancer cell line with constitutive STAT3 activation. This 'STAT3 signature' is likely to comprise those genes that mediate the role of STAT3 in cancer. This signature also allowed me to identify clinical characteristics associated with STAT3 activation in tumors. For instance, I found that this signature is able to distinguish AML from ALL, consistent with STAT3 activation in only the former tumor type. In addition, the presence of this signature predicts poor outcome in patients with high-grade glioma, suggesting that STAT3 activation contributes to the aggressive behavior of these tumors.; I also analyzed the role of STAT3 activation in non-small-cell lung cancers (NSCLC) with mutation of the EGF receptor (EGFR). I demonstrated that STAT3 is constitutively activated in fibroblasts expressing mutant EGFR and in lung cancer cells with naturally occurring EGFR mutations. Further, I showed that STAT3 is required for the transformation of fibroblasts by mutant EGFR, and that STAT3 provides a critical survival signal for lung cancer cells with mutant EGFR. Finally, I analyzed lung tumors with mutant EGFR and showed that they have elevated expression of STAT3 signature genes.; Together the results presented in this dissertation shed light on the mechanism by which persistent STAT3 activation---an abnormality that occurs in a strikingly high proportion of epithelial and hematologic malignancies---contributes to the malignant phenotype. These findings may ultimately lead to the improved diagnosis and treatment of tumors in which STAT3 plays an important role.