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

Abstract

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. One of the most important current issues in breast cancer research is early identification of patients at high risk for relapse coupled with risk-adapted individualized therapy concepts. We have previously shown that the Y-box protein YB-1 is involved in regulating transcription of the P-glycoprotein gene mdr1 and that nuclear localization of YB-1 in human breast cancer is associated with increased P-glycoprotein expression. 1 In the experimental setting, expression of P-glycoprotein confers cross-resistance to a variety of cytotoxic agents differing in structure and mechanism of action (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins and taxanes), resulting in a multidrug-resistant phenotype. 2 However, the functional relevance of P-glycoprotein expression for clinical drug resistance in breast cancer is controversial, since evidence for an association between P-glycoprotein expression and survival is not supported by all investigations. 3 At present, it is still unclear which functions can be directly attributed to P-glycoprotein, or whether P-glycoprotein expression is merely a surrogate marker for other genetic and biolog...

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