RESUMO
X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond initiation of XCI is only beginning to be elucidated. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergence of highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycomb domains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We further demonstrate that loss of XIST and Xi transcriptional instability is common among human breast tumors of poor prognosis. We conclude that XIST is a gatekeeper of human mammary epithelium homeostasis, thus unveiling a paradigm in the control of somatic cell identity with potential consequences for our understanding of gender-specific malignancies.
Assuntos
Complexo Mediador/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/metabolismo , Diferenciação Celular , Epigênese Genética , Humanos , RNA Longo não Codificante/genética , Inativação do Cromossomo XRESUMO
Breast tumors exhibit a hierarchical cellular organization driven by several subpopulations of cancer stem cells (CSCs). These breast CSC subpopulations are able to infinitely self-renew and to differentiate, giving rise to tumor heterogeneity. Accumulating evidence show that breast CSCs resist conventional therapies and i`nitiate tumor relapse. The development of anti-CSCs therapies may therefore greatly improve patient survival. A better elucidation of molecular circuitries involved in stemness would offer new relevant targets. Noncoding RNAs, especially microRNAs and long noncoding RNAs, are regulators of cell identity and are notably found deregulated in breast CSCs. This review will focus on noncoding RNAs involved in CSCs biology during breast cancer initiation, maintenance, therapeutic resistance and metastatic progression. Potential clinical applications using noncoding RNAs as biomarkers or therapies will be discussed.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/genética , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismoRESUMO
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 patient-derived 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 (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. 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.