Oncotarget

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

Daria Fleyshman, Laura Prendergast, Alfiya Safina, Geraldine Paszkiewicz, Mairead Commane, Kelsey Morgan, Kristopher Attwood and Katerina Gurova _

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Oncotarget. 2017; 8:20525-20542. https://doi.org/10.18632/oncotarget.15656

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Abstract

Daria Fleyshman1, Laura Prendergast1, Alfiya Safina1, Geraldine Paszkiewicz1, Mairead Commane1, Kelsey Morgan1, Kristopher Attwood1,2 and Katerina Gurova1

1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

2 Department of Biostatistics, University of Buffalo, SUNY, Buffalo, NY, USA

Correspondence to:

Katerina Gurova, email:

Keywords: FACT, SSRP1, SPT16, curaxin CBL0137, breast cancer

Received: December 29, 2016 Accepted: January 11, 2017 Published: February 23, 2017

Abstract

Although breast cancer (BrCa) may be detected at an early stage, there is a shortage of markers that predict tumor aggressiveness and a lack of targeted therapies. Histone chaperone FACT, expressed in a limited number of normal cells, is overexpressed in different types of cancer, including BrCa. Recently, we found that FACT expression in BrCa correlates with markers of aggressive BrCa, which prompted us to explore the consequences of FACT inhibition in BrCa cells with varying levels of FACT.

FACT inhibition using a small molecule or shRNA caused 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 similar upon equalizing FACT expression. In “high-FACT” cells, FACT supports expression of genes involved in the regulation of cell cycle, DNA replication, maintenance of an undifferentiated cell state and regulated by the activity of several proto-oncogenes. In “low-FACT” cells, the presence of FACT reduces expression of genes encoding enzymes of steroid metabolism that are characteristic of differentiated mammary epithelia.

Thus, we propose that FACT is both a marker and a target of aggressive BrCa cells, whose inhibition results in the death of BrCa or convertion of them to a less aggressive subtype.


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