title: The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway.
abstract: Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ERα-positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. HOXB7 is an ERα-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ERα-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.
authors.affiliation: Breast Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.
authors.forename: Kideok
authors.initials: K
authors.lastname: Jin
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Kong
authors.forename: Tariq
authors.initials: T
authors.lastname: Shah
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Penet
authors.forename: Flonne
authors.initials: F
authors.lastname: Wildes
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Ma
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Xinyan
authors.initials: X
authors.lastname: Wu
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
authors.forename: Tao
authors.initials: T
authors.lastname: Zhu
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D013629:Tamoxifen; C512478:EGFR protein, human; D066246:ErbB Receptors