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Expression of HER2 and Estrogen Receptor Depends upon Nuclear Localization of Y-Box Binding Protein-1 in Human Breast Cancers

¹ Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science; ² Biostatistics Center, Kurume University; ³ Department of Surgery, Kurume University School of Medicine; ⁴ Department of Pathology, Kurume University Hospital, Kurume, Japan; ⁵ National Hospital Organization Kyushu Medical Cancer; ⁶ Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; ⁷ Department of Molecular Biology, University of Occupation and Environmental Health, Kitakyushu, Japan; and ⁸ Department of Genome Biology, Kinki University School of Medicine, Osakasayama, Japan

Requests for reprints: Masayoshi Kage, Department of Pathology, Kurume University Hospital, Kurume 830-0011, Japan. Phone: 81-942-31-7651; Fax: 81-942-31-7651; E-mail: masakage{at}med.kurume-u.ac.jp.

Key Words: YB-1 • ErbB2/HER2 • ER • CXCR4 • breast cancer

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), ERβ, 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 expression in ER-positive, but not ER-negative, breast cancer cell lines. Nuclear YB-1 expression was positively correlated with HER2 (P = 0.0153) and negatively correlated with ER (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. [Cancer Res 2008;68(5):1504–12]