Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells

FACT inhibition, via small molecule or shRNA, lead to reduced growth and viability of all BrCa cells tested. Phenotypic changes were more severe in high FACT cells (death or growth arrest) than in low FACT cells (decreased proliferation). Though inhibition had no effect on the rate of general transcription, expression of individual genes was changed in a cell-specific manner. Initially distinct transcriptional profiles of BrCa cells became almost identical via equalizing FACT expression. We found that in high-FACT cells FACT supports expression of genes involved in the regulation of cell cycle, DNA replication, maintenance of undifferentiated cell state and regulated by the activity of proto-oncogenes, such as Hras, cMyc, E2F family ets. In low-FACT cells presence of FACT reduces expression of genes coding enzymes of steroid metabolism characteristic for the differentiated mammary epithelia. Inhibition of FACT leads to the shift from more aggressive transcriptional program to more benign, accompanied with similar type of phenotypical changes. Thus we propose FACT as a marker to predict aggressiveness of BrCa and as a target to either kill aggressive BrCa cells or to convert them to a less aggressive phenotype.

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