Abstract
BackgroundA subset of breast cancer cells displays increased ability to self-renew and reproduce breast cancer heterogeneity. The characterization of these so-called putative breast tumor-initiating cells (BT-ICs) may open the road for novel therapeutic strategies. As microRNAs (miRNAs) control developmental programs in stem cells, BT-ICs may also rely on specific miRNA profiles for their sustained activity. To explore the notion that miRNAs may have a role in sustaining BT-ICs, we performed a comprehensive profiling of miRNA expression in a model of putative BT-ICs enriched by non-attachment growth conditions.ResultsWe found breast cancer cells grown under non-attachment conditions display a unique pattern of miRNA expression, highlighted by a marked low expression of miR-30 family members relative to parental cells. We further show that miR-30a regulates non-attachment growth. A target screening revealed that miR-30 family redundantly modulates the expression of apoptosis and proliferation-related genes. At least one of these targets, the anti-apoptotic protein AVEN, was able to partially revert the effect of miR-30a overexpression. Finally, overexpression of miR-30a in vivo was associated with reduced breast tumor progression.ConclusionsmiR30-family regulates the growth of breast cancer cells in non-attachment conditions. This is the first analysis of target prediction in a whole family of microRNAs potentially involved in survival of putative BT-ICs.
Highlights
A subset of breast cancer cells displays increased ability to self-renew and reproduce breast cancer heterogeneity
MicroRNA profiling in putative breast tumor-initiating cells (BT-ICs) Because of their role in defining expression programs in development and cancer, we investigated whether miRNA expression displayed a particular profile in putative BT
The non-adherent mammosphere culture system, in which stem-like cells are capable of forming suspended spheres, has been extensively used to enrich cultures for BT-ICs [10]
Summary
A subset of breast cancer cells displays increased ability to self-renew and reproduce breast cancer heterogeneity. As occurs with normal organogenesis and cell differentiation, the selective activation and repression of these pathways may be mediated by microRNAs (miRNAs). These short non-coding RNAs inhibit gene expression by mRNA degradation or translational inhibition [4,5]. Their importance in establishing developmental programs of expression is illustrated by the requirement of miRNA processing proteins like Dicer during embryogenesis [6], and the presence of specific miRNAs in pluripotent cells [7]. We further identified and validated the targets of this family of miRNAs and studied its role in survival of BT-ICs in vitro and in vivo
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