how ever, we found that TGFb had no effect on regulating cofilin activity in breast cancer cells. In our studies, we identified a novel role for p21 in the transcriptional regu lation of TGFb/Smad3 signaling through the interaction of p21 and Smad3 in invasive breast cancer Abiraterone IC50 cells. The interaction between p21 and Smad3 was p/CAF depen dent, but whether this interaction is direct will require further investigation. Furthermore, the effects of p21 on cell migration and invasion are mediated through inter actions with Smad3 and p/CAF, which in turn modulate Smad3 acetylation, DNA binding and transcriptional activity, as well as gene transcription of several TGFb pro invasive downstream target genes.
It will be interest ing to further investigate whether p21 is selective for the pro oncogenic activity of TGFb or whether it is also required for the transcriptional regulation of other types of TGFb responses and target genes. Taken together, our results demonstrate that p21 is both a direct transcrip tional target of TGFb and a co stimulatory factor of Smad3 in regulation of pro invasive genes in breast can cer cells. Finally, we investigated the clinical relevance of TGFb mediated p21/p/CAF pathway in breast cancer. The prognosis of breast carcinomas is related to various clini cal and pathological parameters. Axillary lymph node metastasis is one of the most important prognostic para meters in the absence of distant metastasis. There is a sharp difference in survival rate between patients with positive and negative lymph nodes.
In our studies, we found a significant association of active TGFb/Smad3 sig naling, p21 and p/CAF expression with lymph node posi tivity, making them potential useful prognosis markers for lymph Cilengitide node metastasis. Conclusion In this study, we described a pro invasive function for the cell cycle regulator p21 in human breast cancer. High expression of p21 positively correlated with poor overall and distant metastasis free survival outcomes in breast cancer patients. We identified p21 as a novel downstream regulator of TGFb mediated breast cancer cell migration and invasion. We found p21 to interact with Smad3 and the acetyltransferase p/CAF and to regulate the Smad transcriptional activity, as well as gene transcription of sev eral TGFb induced pro metastatic genes. These results highlight an important role for p21/p/CAF in TGFb induced breast cancer cell migration and invasion at the transcriptional level. Background It is commonly believed that DSBs induced in the gen ome of higher eukaryotes by widely diverse endogenous and exogenous factors and processes are mainly repaired by non homologous end joining.