title: The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene.
abstract: A subset of HER2+ breast cancer patients manifest clinical resistance to trastuzumab. Recently, miR-26a and miR-30b have been identified as trastuzumab response regulators, and their target gene CCNE2 seems to play an important role in resistance to trastuzumab therapy. Cell viability was evaluated in trastuzumab treated HER2+ BT474 wt (sensitive), BT474r (acquired resistance), HCC1954 (innate resistance), and MDA-MB-231 (HER2-) cell lines, and the expression of miR-26a, miR-30b, and their target genes was measured. BT474 wt cell viability decreased by 60% and miR-26a and miR-30b were significantly overexpressed (~3-fold, p = 0.003 and p = 0.002, respectively) after trastuzumab treatment, but no differences were observed in resistant and control cell lines. Overexpression of miR-30b sensitized BT474r cells to trastuzumab (p = 0.01) and CCNE2, was significantly overexpressed after trastuzumab treatment in BT474r cells (p = 0.032), but no significant changes were observed in sensitive cell line. When CCNE2 was silenced BT474r cell sensitivity to trastuzumab increased (p = 0.03). Thus, the molecular mechanism of trastuzumab action in BT474 cell line may be regulated by miR-26a and miR-30b and CCNE2 overexpression might play an important role in acquired trastuzumab resistance in HER2+ breast cancer given that resistance was diminished when CCNE2 was silenced.
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tormo
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Adam-Artigues
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ballester
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Pineda
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zazo
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: González-Alonso
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.|Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.|Pompeu Fabra University, 08002 Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Cancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.|Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.affiliation: Pathology Department, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.|Oncology and Hematology Department, Hospital Clínico Universitario, 46010 Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Eroles
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016213:Cyclins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C503688:CCNE2 protein, human; C528163:MIRN26 microRNA, human; C546086:MIRN30b microRNA, human