Expression of HER2 and estrogen receptor alpha depends upon nuclear localization of Y-box binding protein-1 in human breast cancers.

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.

• Authors: Teruhiko Fujii, Akihiko Kawahara, Yuji Basaki, Satoshi Hattori, Kazutaka Nakashima, Kenji Nakano, Kazuo Shirouzu, Kimitoshi Kohno, Takashi Yanagawa, Hideaki Yamana, Kazuto Nishio, Mayumi Ono, Michihiko Kuwano, Masayoshi Kage
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 5 Pg. 1504-12 (Mar 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18316615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Estrogen Receptor alpha
• Y-Box-Binding Protein 1
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Disease-Free Survival
• Estrogen Receptor alpha (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Models, Biological
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Receptor, ErbB-2 (metabolism)
• Regression Analysis
• Y-Box-Binding Protein 1 (biosynthesis)