Abstract
In our present study, we examined whether nuclear localization of Y-box binding protein-1 (YB-1) is associated with the expression of epidermal growth factor receptors (EGFR), hormone receptors, and other molecules affecting breast cancer prognosis. The expression of nuclear YB-1, clinicopathologic findings, and molecular markers [EGFR, HER2, estrogen receptor (ER)alpha, ER beta, progesterone receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), phosphorylated Akt, and major vault protein/lung resistance protein] were immunohistochemically analyzed. The association of the expression of nuclear YB-1 and the molecular markers was examined in breast cancer cell lines using microarrays, quantitative real-time PCR, and Western blot analyses. Knockdown of YB-1 with siRNA significantly reduced EGFR, HER2, and ER alpha expression in ER alpha-positive, but not ER alpha-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER alpha (P = 0.0122) and CXCR4 (P = 0.0166) in human breast cancer clinical specimens but was not correlated with EGFR expression. Nuclear YB-1 expression was an independent prognostic factor for overall (P = 0.0139) and progression-free (P = 0.0280) survival. In conclusion, nuclear YB-1 expression might be essential for the acquisition of malignant characteristics via HER2-Akt-dependent pathways in breast cancer patients. The nuclear localization of YB-1 could be an important therapeutic target against not only multidrug resistance but also tumor growth dependent on HER2 and ER alpha.
Highlights
Nuclear localization of Y-box binding protein-1 (YB-1) is required for its transcriptional control of multidrug resistance–related genes and for its action in repairing DNA damage induced by anticancer agents and radiation in cancer cells; as a result of these actions, it is responsible for the acquisition of global drug resistance to a wideNote: Supplementary data for this article are available at Cancer Research Online.Nuclear expression of YB-1 is often associated with poor prognosis in various human malignancies, including breast cancer [3, 6], ovarian cancer [8, 11], synovial sarcoma [5], and lung cancer [14]
We assessed whether the expression of epidermal growth factor (EGF) receptor (EGFR) and ErbB2/HER2 was affected by YB-1 in breast cancers, as this might influence prognosis
We developed two independent approaches to identify which genes are under the control of YB-1 in human breast cancer cells
Summary
Nuclear localization of Y-box binding protein-1 (YB-1) is required for its transcriptional control of multidrug resistance–related genes and for its action in repairing DNA damage induced by anticancer agents and radiation in cancer cells; as a result of these actions, it is responsible for the acquisition of global drug resistance to a wideNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Nuclear expression of YB-1 is often associated with poor prognosis in various human malignancies, including breast cancer [3, 6], ovarian cancer [8, 11], synovial sarcoma [5], and lung cancer [14]. In a study using molecular profiling, Faury et al [15] recently showed that overexpression of YB-1 is a novel prognostic target for pediatric glioblastoma; the intracellular localization of YB-1 was not determined These clinical studies suggest the close involvement of YB-1 in the acquisition of global drug resistance [2]; it remains unclear whether the association of YB-1 with poor prognosis is due to this effect, as YB-1 nuclear localization is a prognostic marker irrespective of P-glycoprotein expression [8, 14, 16]. Jurchott et al [19] reported that nuclear localization of YB-1 was induced during G1-S phase transition, accompanied by increased expression of cyclin A and B These studies suggest a close link between YB-1 expression and the growth potential of breast cancer cells, which might contribute to poor prognosis. Sutherland et al [24] have shown that breast cancer cells with defective nuclear localization of YB-1 multiply slowly in monolayers and during anchorage-independent growth
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