title: HOXB7 Is an ERα Cofactor in the Activation of HER2 and Multiple ER Target Genes Leading to Endocrine Resistance.
abstract: Why breast cancers become resistant to tamoxifen despite continued expression of the estrogen receptor-α (ERα) and what factors are responsible for high HER2 expression in these tumors remains an enigma. HOXB7 chromatin immunoprecipitation analysis followed by validation showed that HOXB7 physically interacts with ERα, and that the HOXB7-ERα complex enhances transcription of many ERα target genes, including HER2. Investigating strategies for controlling HOXB7, our studies revealed that MYC, stabilized via phosphorylation mediated by EGFR-HER2 signaling, inhibits transcription of miR-196a, a HOXB7 repressor. This leads to increased expression of HOXB7, ER target genes, and HER2. Repressing MYC using small-molecule inhibitors reverses these events and causes regression of breast cancer xenografts. The MYC-HOXB7-HER2 signaling pathway is eminently targetable in endocrine-resistant breast cancer.
  
  
  CONCLUSIONS
  HOXB7 acts as an ERα cofactor regulating a myriad of ER target genes, including HER2, in tamoxifen-resistant breast cancer. HOXB7 expression is controlled by MYC via transcriptional regulation of the HOXB7 repressor miR-196a; consequently, antagonists of MYC cause reversal of selective ER modulator resistance both in vitro and in vivo.
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kideok
authors.initials: K
authors.lastname: Jin
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sunju
authors.initials: S
authors.lastname: Park
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Wei Wen
authors.initials: WW
authors.lastname: Teo
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Preethi
authors.initials: P
authors.lastname: Korangath
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sean Soonweng
authors.initials: SS
authors.lastname: Cho
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University, Bloomington, Indiana.
authors.forename: Chirayu Pankaj
authors.initials: CP
authors.lastname: Goswami
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University, Bloomington, Indiana.
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Leigh-Ann
authors.initials: LA
authors.lastname: Cruz
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ekram
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. saras@jhmi.edu.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D011379:Prognosis; D011485:Protein Binding; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D018398:Homeodomain Proteins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C490538:HOXB7 protein, human; C542543:MIRN196 microRNA, human