Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1.
Intrinsic or acquired resistance to chemotherapy is responsible for failure of current treatment regimens in breast cancer patients. The Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug-resistant tumor phenotype. In human breast cancer, overexpression and nuclear localization of YB-1 is associated with upregulation of P-glycoprotein. In our pilot study, we analyzed the clinical relevance of YB-1 expression in breast cancer (n = 83) after a median follow-up of 61 months and compared it with tumor-biologic factors already used for clinical risk-group discrimination, i.e., HER2, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1). High YB-1 expression in tumor tissue and surrounding benign breast epithelial cells was significantly associated with poor patient outcome. In patients who received postoperative chemotherapy, the 5-year relapse rate was 66% in patients with high YB-1 expression. In contrast, in patients with low YB-1 expressions, no relapse has been observed so far. YB-1 expression thus indicates clinical drug resistance in breast cancer. Moreover, YB-1 correlates with breast cancer aggressiveness: in patients not treated with postoperative chemotherapy, those with low YB-1 expression are still free of disease, whereas the 5-year relapse rate in those with high YB-1 was 30%. There was no significant correlation between YB-1 expression and either HER2 expression or uPA and PAI-1 levels. Risk-group assessment achieved by YB-1 differed significantly from that by HER2 or uPA/PAI-1. In conclusion, YB-1 demonstrated prognostic and predictive significance in breast cancer by identifying high-risk patients in both the presence and absence of postoperative chemotherapy, independent of tumor-biologic factors currently available for clinical decision making.
Janz
Martin
M
Department of Cell Growth and Differentiation, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Harbeck
Nadia
N
Dettmar
Peer
P
Berger
Ursula
U
Schmidt
Anja
A
Jürchott
Karsten
K
Schmitt
Manfred
M
Royer
Hans-Dieter
HD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D002455:Cell Division; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008593:Menopause; D008875:Middle Aged; D051839:NFI Transcription Factors; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017698:Postmenopause; D017697:Premenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D017395:Plasminogen Activator Inhibitor 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D014568:Urokinase-Type Plasminogen Activator; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human