We speculate that over expression of OCT4 inside a subpopulation of cells from the mammary gland was capable to sustain these cells inside a locked in and undifferentiated state, limiting them from undergoing downstream lineage specification gene professional grams. This explanation is steady with a mouse model of OCT4 cDNA overexpression, which demon strates that OCT4 generates hyperplasia on the skin and colon by possibly targeting progenitor cells. Although the exact mechanism by which OCT4 trig gers the TIC like phenotype wants even more investigation, we speculate that gain of self renewal ability is really a com plex genome wide phenomenon that needs endogen ous reactivation of the TIC self renewal TF network. This model is consistent with our microarray information, which demonstrate that direct targets of NANOG, OCT4, and SOX2, which are reasonably well characterized in hESCs, can also be differentially regulated in OTBCs relative to their parental lines.
Consequently, OTBCs could mimic or maybe corrupt a primary specific Src inhibitor hESC self renewal TF network, which calls for protein protein associations acting within a combinatorial manner at precise promoter websites. The characterization of this TIC like TF network and particularly how this protein network dif fers from hESCs will need even more review. In the TIC, this network may well similarly involve associations in between TFs, for example OCT4 and NANOG, and co activator or co repressor complexes also as chromatin remode lers. This combinatorial occupancy of factors at precise promoters could lead to the activation of potential oncogenes and self renewal gene plans at the same time as the repression of selected tumor suppressor genes. Importantly, our information propose that NOS targets are regulated in a different way in TICs relative to hESCs. DKK1, an antagonist in the Wnt signaling pathway, is abun dantly expressed in hESCs.
In contrast, this target was noticed downregulated in OTBCs. Indeed, DKK1 is actually a secreted tumor suppressor informative post in breast cancer. Wnt signaling in breast cancer has become linked to EMT by means of stabilization of Snail and upregulation of your EMT TFs SLUG and TWIST. Overexpres sion of DKK1 within a breast cancer cell line resulted in an inhibition of self renewal potential. Thus, downregulation with the NOS target DKK1 in OTBCs is steady with get of self renewal ability and mesenchymal character istics via the upregulation of EMT TFs. In hESCs, OCT4 represses TFs associated with pattern specification, just like homeobox containing proteins. In contrast, homeobox containing TFs had been extremely enriched in our OTBC upregulated gene signature. The homeobox TF SIX1 was found upregulated inside the OTBCs relative to parental lines. Overexpression of SIX1 from the mouse mammary gland promoted an expan sion of stem progenitor cells and subsequent tumor growth. Inside a parallel study, Micalizzi and col leagues reported that overexpression of SIX1 also facilitated breast cancer metastasis by induction of EMT.