The Histone Deacetylase Inhibitor Abexinostat Induces Cancer Stem Cells Differentiation in Breast Cancer with Low Xist Expression

Abstract

Purpose: Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies.Experimental Design: We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patientderived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers.Results: We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (Xinactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population.Conclusions: Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment.

Urinary Xist is a potential biomarker for membranous nephropathy

“…For example, increased Xist levels in the brain were observed when fetal mice were exposed to diesel exhaust [28]. Similar increases in Xist expression were also found in response to HDAC inhibitor treatment for breast cancer, or chemotherapy for ovarian cancer [29,30]. These findings raised an interesting question of whether Xist can protect cell against damage.…”

Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin

“…It has been suggested that HDAC inhibitors may be effective in the treatment of breast cancer because of their ability to target BCSCs decreasing proliferation of ALDH1-positive cells and decreasing the formation of breast cancer mammospheres [47]. In light of all of these studies, we determined the effect of LBH589 on TNBC cell lines with BCSC properties.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…HDAC inhibitors have been found to be beneficial in BC therapy, as they target BC stem cells, have anti-proliferative effects on aldehyde dehydrogenase 1 (ALDH1)-positive cells, and suppress the formation of BC mammospheres (120). Also, ALDH1 has been associated with TNBC, so ALDH1 can be used as a BC stem cell marker in TNBC (121,122).…”