title: An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis.
abstract: Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2(+) cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically in concert with a cascade of MLL2-associating epigenetic regulators to dampen sensitivity of the cancer cells to lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Matkar
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Paras
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Xiamen University College of Medicine, Xiangan District, Xiamen 361006, PR China.
authors.forename: Shubin
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Buddha
authors.initials: B
authors.lastname: Gurung
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Bryson W
authors.initials: BW
authors.lastname: Katona
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Abdul Bari
authors.initials: AB
authors.lastname: Muhammad
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Xiang-Cheng
authors.initials: XC
authors.lastname: Kong
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Xiamen University College of Medicine, Xiangan District, Xiamen 361006, PR China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Medicine, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, 412 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: huax@mail.med.upenn.edu.
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D001569:Benzodiazepines; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D000077341:Lapatinib; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C120898:KMT2D protein, human; C489427:MYC protein, human; C554645:molibresib; C508053:ERBB2 protein, human