title: A novel EGR-1 dependent mechanism for YB-1 modulation of paclitaxel response in a triple negative breast cancer cell line.
abstract: Chemotherapy with taxanes such as paclitaxel (PTX) is a key component of triple negative breast cancer (TNBC) treatment. PTX is used in combination with other drugs in both the adjuvant setting and in advanced breast cancer. Because a proportion of patients respond poorly to PTX or relapse after its use, a greater understanding of the mechanisms conferring resistance to PTX is required. One protein shown to be involved in drug resistance is Y-box binding protein 1 (YB-1). High levels of YB-1 have previously been associated with resistance to PTX in TNBCs. In this study, we aimed to determine mechanisms by which YB-1 confers PTX resistance. We generated isogenic TNBC cell lines that differed by YB-1 levels and treated these with PTX. Using microarray analysis, we identified EGR1 as a potential target of YB-1. We found that low EGR1 mRNA levels are associated with poor breast cancer patient prognosis, and that EGR1 and YBX1 mRNA expression was inversely correlated in a TNBC line and in a proportion of TNBC tumours. Reducing the levels of EGR1 caused TNBC cells to become more resistant to PTX. Given that PTX targets cycling cells, we propose a model whereby high YB-1 levels in some TNBC cells can lead to reduced levels of EGR1, which in turn promotes slow cell cycling and resistance to PTX. Therefore YB-1 and EGR1 levels are biologically linked and may provide a biomarker for TNBC response to PTX.
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
authors.forename: Annette
authors.initials: A
authors.lastname: Lasham
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
authors.forename: Sunali Y
authors.initials: SY
authors.lastname: Mehta
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Fitzgerald
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Adele G
authors.initials: AG
authors.lastname: Woolley
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: James I
authors.initials: JI
authors.lastname: Hearn
authors.affiliation: Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.|Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Systems Biology Laboratory, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Hurley
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Igor
authors.initials: I
authors.lastname: Ruza
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Michael
authors.initials: M
authors.lastname: Algie
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Shelling
authors.affiliation: Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.|Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Braithwaite
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D017239:Paclitaxel / Q000494:pharmacology*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D051840:Y-Box-Binding Protein 1; D017239:Paclitaxel
keywords: ABCB1; DUSP4; MDR1; Y-box binding protein 1; early growth response 1