Expression of HER2 and estrogen receptor alpha depends upon nuclear localization of Y-box binding protein-1 in human breast cancers.
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.
Fujii
Teruhiko
T
Center for Innovative Cancer Therapy of the 21st Century Center of Excellence Program for Medical Science, Department of Surgery, Kurume University School of Medicine, Kurume, Japan.
Kawahara
Akihiko
A
Basaki
Yuji
Y
Hattori
Satoshi
S
Nakashima
Kazutaka
K
Nakano
Kenji
K
Shirouzu
Kazuo
K
Kohno
Kimitoshi
K
Yanagawa
Takashi
T
Yamana
Hideaki
H
Nishio
Kazuto
K
Ono
Mayumi
M
Kuwano
Michihiko
M
Kage
Masayoshi
M
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012044:Regression Analysis; D051840:Y-Box-Binding Protein 1 / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D051840:Y-Box-Binding Protein 1; C508053:ERBB2 protein, human