title: MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer.
abstract: Breast cancer remains one of the leading causes of cancer mortality among women. It has been proved that the onset of cancer depends on a very small pool of tumor cells with a phenotype similar to that of normal adult stem cells. Cancer stem cells (CSC) possess self-renewal and multilineage differentiation potential as well as a robust ability to sustain tumorigenesis. Evidence suggests that CSCs contribute to chemotherapy resistance and to survival under hypoxic conditions. Interestingly, hypoxia in turn regulates self-renewal in CSCs and these effects may be primarily mediated by hypoxic inducible factors (HIFs). Recently, microRNAs (miRNAs) have emerged as critical players in the maintenance of pluripotency and self-renewal in normal and cancer stem cells. Here, we demonstrate that miR-24 is upregulated in breast CSCs and that its overexpression increases the number of mammospheres and the expression of stem cell markers. MiR-24 also induces apoptosis resistance through the regulation of BimL expression. Moreover, we identify a new miR-24 target, FIH1, which promotes HIFα degradation: miR-24 increases under hypoxic conditions, causing downregulation of FIH1 and upregulation of HIF1α. In conclusion, miR-24 hampers chemotherapy-induced apoptosis in breast CSCs and increases cell resistance to hypoxic conditions through an FIH1-HIFα pathway.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Roscigno
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Puoti
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Giordano
authors.affiliation: IRCCS-SDN, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Donnarumma
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Russo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Affinito
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Adamo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Quintavalle
authors.affiliation: Department of Pathobiology and Medical Biotechnology, University of Palermo, Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.affiliation: CIC bioGUNE, Centre for Cooperative Research in Biosciences, Derio, Spain.
authors.forename: Maria dM
authors.initials: MD
authors.lastname: Vivanco
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D002945:Cisplatin
keywords: BimL; FIH1; breast cancer; cancer stem cells; microRNAs