Tumor cells inherit from their normal precursors an extensive stress response machinery that is critical for survival in response to challenges including oxidative stress, wounding and shear stress. Kruppel-like transcription factors, including KLF4 and KLF5, are rarely affected by genetic alteration during tumorigenesis, but compose key components of the stress response machinery in normal and tumor cells and interact with critical survival pathways, including RAS, p53, survivin and the BCL2 family of cell death regulators. Within tumor cells KLF4 and KLF5 play key roles in tumor cell fate, regulating cell proliferation, cell survival and the tumor initiating properties of cancer stem-like cells. These factors can be preferentially expressed in embryonic stem cells or cancer stem-like cells. Indeed, specific KLFs represent key components of a cross regulating pluripotency network in embryonic stem cells, and induce pluripotency when coexpressed in adult cells with other Yamanaka factors. Suggesting analogies between this pluripotency network and the cancer cell adaptive reprogramming that occurs in response to targeted therapy, recent studies link KLF4 and KLF5 to adaptive prosurvival signaling responses induced by HER2-targeted therapy. We review literature supporting KLFs as shared mechanisms in stress adaptation and cellular reprogramming and address the therapeutic implications.

The high mobility group box protein SOX9 and the GLI1 transcription factor play protumorigenic roles in pancreatic ductal adenocarcinoma (PDA). In Kras transgenic mice, each of these factors are crucial for the development of PDA precursor lesions. SOX9 transcription is directly regulated by GLI1, but how SOX9 functions downstream of GLI1 is unclear. We observed positive feedback, such that SOX9-deficient PDA cells have severely repressed levels of endogenous GLI1, attributed to loss of GLI1 protein stability. SOX9 associated with the F-box domain of the SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase component, b-TrCP (also known as F-box/WD repeat-containing protein 1A), and suppressed its association with SKP1 and GLI1, a substrate of SCF-b-TrCP. SOX9 also tethered b-TrCP within the nucleus and promoted its degradation. SOX9 bound to b-TrCP through the SOX9 C-terminal PQA/S domain that mediates transcriptional activation. Suppression of b-TrCP in SOX9-deficient PDA cells restored GLI1 levels and promoted SOX9-dependent cancer stem cell properties. These studies identify SOX9-GLI1 positive feedback as a major determinant of GLI1 protein stability and implicate b-TrCP as a latent SOX9-bound tumor suppressor with the potential to degrade oncogenic proteins in tumor cells.

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rates of OS and DMFS were similar with 45 Gy and <45 Gy but 2-and 5-year EFS rates were significantly higher with 45 Gy (82% and 66% vs. 76% and 50% with <45 Gy, p Z 0.006). The rates of OS, DMFS, and EFS were significantly lower in patients with a tumor diameter 8 mm. In patients with a tumor depth 8 mm, the rates of DMFS and EFS were significantly lower. In patients with a tumor volume <600 mm 3 , the rates of OS, DMFS, and EFS were significantly higher. Among patients that received 45 Gy, the ones with a tumor volume <600 cm 3 had significantly higher rates of DMFS and EFS but OS was similar. In multivariate analysis, no prognostic factors were found for DMFS. However, for OS and EFS >8 mm basal tumor diameter (relative risk [RR] Z 1.6, 95% confidence interval [CI] Z 1.92-3.12, p Z 0.09; and RR Z 1.8, 95% CI Z 1.15-2.81, p Z 0.01), for EFS >8 mm depth (RR Z 1.6, 95% CI Z 1.03-2.4, p Z 0.03), and 45 Gy dose (RR Z 1.4, 95% CI Z 0.9-2.08, p Z 0.06) were negative prognostic factors. SRS/FSRT-related late toxicity was significantly higher in patients with a basal tumor diameter >8 mm and depth >8 mm (p Z 0.001 and p Z 0.04, respectively). Conclusion: Total SRS/FSRT dose and tumor diameter and depth were found prognostic factors for EFS. Toxicity rate was higher in patients with a higher tumor depth and basal diameter.