First name
Chiara
Last name
Tordonato
Year of Study
Thesis Title
A novel microRNA family as molecular determinant in mammary stem cells
Thesis Abstract
MicroRNAs (miRNAs) are an evolutionarily conserved class of small (18-22 nucleotides) noncoding RNAs involved in the regulation of a variety of cellular and developmental processes. MiRNAs recently emerged as key regulators of stem cells (SCs) cell-fate. In breast, forced expression of miR-200 or let-7 could inhibit both normal and cancer SCs by silencing self-renewal determinants. Intriguingly, these miRNAs are poorly, or not, expressed in the SC compartment and their function is mainly achieved through the induction of differentiation, suggesting that other miRNAs could be required specifically in SCs to maintain their identity.
We aimed at identifying those miRNAs specifically expressed in mammary SCs by exploiting an innovative technique for the isolation of quasi-pure SCs/CSCs. We, thus, identified a miRNA family highly enriched in SCs isolated from both normal and cancer human primary samples and mouse mammary epithelia. High levels of this miR-family were also found in CSCs obtained from human primary biopsies and correlated with tumors of the basal subtype and with an elevated CSC content. Depletion of these miRNAs impaired self-renewal of both normal SCs/ and CSCs, as measured by serial mammosphere assay and by in vivo tumorigenicity assay. We employed a global transcriptomic approach to assess the effects of the loss of this miRNAs in stem cell biology, coupled with target predictions. We revealed that the gene expression program of “stemness” is specifically dependent on the expression of this miR-family and regulated by the interaction of these miRNAs with multiple genes critical for self-renewal and cell fate determination.
We aimed at identifying those miRNAs specifically expressed in mammary SCs by exploiting an innovative technique for the isolation of quasi-pure SCs/CSCs. We, thus, identified a miRNA family highly enriched in SCs isolated from both normal and cancer human primary samples and mouse mammary epithelia. High levels of this miR-family were also found in CSCs obtained from human primary biopsies and correlated with tumors of the basal subtype and with an elevated CSC content. Depletion of these miRNAs impaired self-renewal of both normal SCs/ and CSCs, as measured by serial mammosphere assay and by in vivo tumorigenicity assay. We employed a global transcriptomic approach to assess the effects of the loss of this miRNAs in stem cell biology, coupled with target predictions. We revealed that the gene expression program of “stemness” is specifically dependent on the expression of this miR-family and regulated by the interaction of these miRNAs with multiple genes critical for self-renewal and cell fate determination.
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