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

• Published in: Clinical cancer research 2013-12, Vol.19 (23), p.6520-6531
• Main Authors: SALVADOR, Marion A, WICINSKI, Julien, COLLETTE, Yves, BIRNBAUM, Daniel, CHARAFE-JAUFFRET, Emmanuelle, GINESTIER, Christophe, CABAUD, Olivier, TOIRON, Yves, FINETTI, Pascal, JOSSELIN, Emmanuelle, LELIEVRE, Hélène, KRAUS-BERTHIER, Laurence, DEPIL, Stéphane, BERTUCCI, François
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzofurans - pharmacology; Benzofurans - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Cycle - drug effects; Cell Differentiation - drug effects; Cell Line, Tumor; Cellular Biology; Drug Resistance, Neoplasm; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Inhibitory Concentration 50; Life Sciences; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - physiology; Pharmacology. Drug treatments; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-0877

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. 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 patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers. 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 (X-inactive 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. 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.