The Role and Expression Pattern of TET1 in Breast Cancer

Date
2019-12-18
Authors
Mahmoud Ali Mousa Al-Zahayqa
محمود علي موسى الزحايقة
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Abstract
Cancer is a genetic disease. Mutations and epigenetic alterations such as aberrant DNA methylation which results in altered gene expression is evident in all cancers studied, and is likely responsible for its major hallmarks. Methylation is maintained by DNA methyltransferases, however, methylation can be reversed by mechanisms that are poorly understood. Recently, functional demethylation was linked to hydroxylation of 5hmC by the TET family. TET1 is the most reduced member in a variety of human malignancies, suggesting a tumor suppressor function for this protein. In addition, published research showed controversial conclusions about TET1 function in breast cancer. Moreover, recent evidence showed that TET1 has more than one isoform. Thus, our hypothesis proposes the different TET1 isoforms may play different roles in breast cancer through differential expression pattern in different transformation contexts. In the present study, we tested the expression level and localization of TET1 enzyme in breast cancer samples using IHC, and the expression level using relative qRT-PCR in different breast cancer cell lines under different contexts. In addition, we tested the expression pattern of different TET1 isoforms using in vitro and in vivo cell transformation models. We also tested the effect of TET1 overexpression in MDA MB231 cells using lentivirus vector containing TET1 coding sequence on various cancer hallmarks. Our results demonstrate that TET1 has differential expression pattern in breast cancer embedded tissue samples compared to normal tissue. In addition, TET1 expression correlated with the differentiation level. From our hormone experiments, and in vitro as well as in vivo transformation studies, we clearly showed that different TET1 isoforms are differentially expressed under different physiological and transformation contexts, and different TET1 isoforms having different distribution pattern. Finally, we proved that TET1 full length is a tumor suppressor gene. In conclusion, our study demonstrates the role of TET1 in breast cancer is not straight forward one and this necessitates future studies to better characterize the TET1 function in breast cancer initiation and progression
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