Transcriptional connections between embryonic stem, adult stem and tumor phenotypes

Embryonic stem (ES) cells pluripotency is maintained by complex molecular networks that involve limited numbers of transcription factors along with epigenetic regulators, such as Polycomb and Trithorax genes It is currently broadly accepted that tumors may derive from the transformation of adult stem cells (ASC)(cancer stem cell theory), but a few paper in the last two or three years, have been revealing that tumors share the transcriptional phenotype with ES cells (Visvader J. et al 2008). Kim et al (Kim et al 2010) have recently demonstrated that the overall ES transcriptional program can be further divided in distinct “modules”, that involve minimally over-lapping networks and that may be finely regulated to function differently in ES, ASC and tumors. These modules are: 1) CORE module: includes pluripotency transcriptional factors such as Oct4, Sox2, etc..; 2) PRC module: includes polycomb genes; 3) MYC-centered module, including molecules interacting with c-Myc. Our work focused the study of how the molecules comprised in these modules may be differentially regulated to ultimately determine the stem and/or tumor phenotype and whether their transcriptional profile may be effective in diagnosis of tumor aggressiveness and therapy outcome. In this work we have compared ESC, ASC and breast tumors for the expression profile of varied gene sets identifying the “stem” phenotype. We found that: 1) ASC exhibit a transcriptional profile for these genes that is intermediate between that of ESC and that of terminally differentiated tissues; 2) ASC exhibit a transcriptional profile for these genes that is intermediate between that of Tumors and that of normal, terminally differentiated tissues; 3) the most aggressive breast cancers (basal-like intrinsic sub-types) over-expressed all the Kim’s ES modules compared to the less aggressive ones, although only the enrichment of the Myc module resulted statistically significant.