To gain a mechanistic understanding of how OCT4 immortalized and transformed the target cells, we per formed gene expression microarray experiments. The comparison of genome wide transcriptional profiles selleckchem Pacritinib of OTBCs with their parental lines revealed a gene signa ture that was over represented in the newly discovered claudin low intrinsic subtype of breast cancer. Claudin low carcinomas were recently identified by Herschko witz and colleagues and further characterized by using a large database of human breast tumors and cell lines. Although claudin low tumors are rela Inhibitors,Modulators,Libraries tively rare, they are associated with poor patient survival. Claudin low carcinomas uniquely express low levels of tight and adherent junction genes, including claudins and E cadherin. Hallmarks of these tumors include enrichment in EMT markers and putative TIC markers.
Recent genome wide analysis suggests that this newly discovered Inhibitors,Modulators,Libraries intrinsic subtype of breast cancer is closely related to putative EpCAM mammary stem cells. Basal like breast cancer, which is associated with muta tions in the tumor suppressor gene BRCA1, appears to be more closely related to an EpCAM luminal restricted progenitor cell population. Further support for the hypothesis that claudin low carcinomas may arise from primitive stem Inhibitors,Modulators,Libraries progenitor cells is provided by clinical data, which show that TICs are enriched in patients with breast cancer after neo adjuvant therapy. Recent gene expression microarray analyses of these TICs revealed enrichment in EMT gene signatures. Similarly, OTBCs Inhibitors,Modulators,Libraries exhibited enrichment in mesenchymal markers and TIC features.
Compared with their parental lines, OTBCs upregulated the EMT TFs SNAIL, TWIST, and ZEB1 2 as well as microRNAs asso ciated with EMT, such as miR 200s Inhibitors,Modulators,Libraries family members and miR 205. EMT has been associated with stemness. The forced expression of EMT TFs in immortalized breast epithelial cells led to stem cell like characteristics and induction of TIC surface antigens. Recently, ectopic expression of OCT4 and NANOG was shown to enhance malignancy and induce EMT in lung adenocarcinoma cell lines. This finding con firms our results that link OCT4 and NANOG as poten tial oncogenes, which drive EMT processes in the mammary tissue. OCT4 expression was recently demon strated in the MMTV Wnt1 mouse models of breast cancer.
Recent work on epithelial ovarian cancer has shown that pluripotency TFs, such as OCT4 and NANOG, are overexpressed in poorly differentiated epithelial ovarian cancers. Furthermore, the RNAi knockdown of OCT4 in these cells prevented or blocked their ability to generate spheroids. Likewise, a similar report in the MCF CHIR99021 IC50 7 breast cancer cell line demonstrated that the knockdown of OCT4 induced tumor cell death. Our loss of function studies also outlined the crucial role of OCT4 and its downstream targets in maintaining self renewal and EMT in our OTBC lines. We found that the hESC NOS target ZIC1 was upregulated in all OTBCs.