title: miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance.
abstract: The ErbB tyrosine kinase receptor family has been shown to have an important role in tumorigenesis, and the expression of its receptor members is frequently deregulated in many types of solid tumors. Various drugs targeting these receptors have been approved for cancer treatment. Particularly, in breast cancer, anti-Her2/EGFR molecules represent the standard therapy for Her2-positive malignancies. However, in a number of cases, the tumor relapses or progresses thus suggesting that not all cancer cells have been targeted. One possibility is that a subset of cells capable of regenerating the tumor, such as cancer stem cells (CSCs), may not respond to these therapeutic agents. Accumulating evidences indicate that miR-205-5p is significantly downregulated in breast tumors compared with normal breast tissue and acts as a tumor suppressor directly targeting oncogenes such as Zeb1 and ErbB3. In this study, we report that miR-205-5p is highly expressed in BCSCs and represses directly ERBB2 and indirectly EGFR leading to resistance to targeted therapy. Furthermore, we show that miR-205-5p directly regulates the expression of p63 which is in turn involved in the EGFR expression suggesting a miR-205/p63/EGFR regulation.
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Cola
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Volpe
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Budani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.identifier: 0000000215956887
authors.initials: M
authors.lastname: Ferracin
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Lattanzio
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Turdo
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: D'Agostino
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Capone
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Di Ilio
authors.affiliation: 1] Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy [2] Mediapharma s.r.l., Via dei Vestini, Chieti, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sala
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Piantelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Negrini
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Veronese
authors.affiliation: Department of Experimental and Clinical Sciences, Aging Research Center (Ce.S.I.), University G. D'Annunzio, Chieti-Pescara, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000068878:Trastuzumab / Q000008:administration & dosage; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D066246:ErbB Receptors; D000077341:Lapatinib; D035683:MicroRNAs; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C534425:MIR205, human; C115051:TP63 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human