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.
Highlights
Advancements in the screening and diagnosis of breast cancer (BrCa) have led to the increased detection of tumors at a pre-invasive or early invasive stage, commonly leading to clinical intervention before the disease has a chance to spread
We have found that levels of FAcilitates Chromatin Transcription (FACT) complex in BrCa correlate with poor overall survival, presence of clinical markers of bad prognosis, and high probability of metastatic disease [1, 2]
Inhibition of FACT is lethal for BrCa cells with high basal FACT expression Expression of both FACT subunits, SSRP1 and SPT16, is significantly elevated in BrCa samples versus normal mammary epithelial cells [1, 25]
Summary
Advancements in the screening and diagnosis of breast cancer (BrCa) have led to the increased detection of tumors at a pre-invasive or early invasive stage, commonly leading to clinical intervention before the disease has a chance to spread. There are several subtypes of BrCa defined by the presence of molecular markers, such as Her and hormone receptors, which are used to predict the aggressive potential of BrCa and dictate therapeutic intervention. Though these markers have revolutionized the way clinicians approach BrCa, there is still significant heterogeneity within subtypes, which leads to the overtreatment or under-treatment of many patients whose tumors do not progress as projected by their molecular subtype. Knockdown of FACT using RNAi inhibits tumor transformation and compromises the viability of tumor cells, but is well tolerated by non-tumor cells [1]
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