The Expression Pattern of TET Enzymes in Breast Cancer

The TET family of enzymes oxidate methylated DNA (5mC) to 5hmC and are reportedly down-regulated in many cancers. TET1 and TET2, but not TET3, are highly expressed in embryonic stem cells (ESCs), and with differentiation their expression is repressed. Despite this, all three enzymes are expressed in certain differentiated tissues and are often enriched at gene regulatory regions where they likely play crucial roles in determining gene expression, and may act as tumor suppressors. In breast cancer, TET1 was reported to suppress tumor growth and metastasis, and its depletion facilitated cancer invasion, while correlating with poor survival. However our histological studies indicate that all three TET enzymes are not necessarily down-regulated in breast tumors, but their cellular localization appears altered, suggesting that they may be regulated differently than in normal tissues. All three Tet enzymes are apparently regulated by various post-translational modifications, and appear in the databases in several isoforms. We therefore hypothesized that their behaviour in breast tumor cells might be due to their different regulation arising from the expression of distinct protein variants. However in normal mammary tissue from young and old mice, we found that Tet1 is expressed as an alternative variant which differed from the better studied isoform expressed in ESCs. Our initial studies suggest that mouse mammary tumors might express the ESC isoform of the Tet1 protein, reinforcing the idea that the protein may be differently regulated in tumor cells due to the inclusion of distinct domains and/or PTM targeting sites. We are currently investigating the TET isoforms expressed in human breast tumours in order to study how their cellular localization and function might be regulated.