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Disruption of the Y-Box Binding Protein-1 Results in Suppression of the Epidermal Growth Factor Receptor and HER-2

¹ Laboratory for Oncogenomic Research, Department of Pediatrics, Child and Family Research Institute, University of British Columbia; ² Genetic Pathology Evaluation Center of the Prostate Research Center, Vancouver General Hospital and BC Cancer Agency, Vancouver, British Columbia, Canada; ³ Wake Forest University, Winston Salem, North Carolina; ⁴ University Hospital of the RWTH, Aachen, Germany; and ⁵ University Hospital of Tuebingen, Tuebingen, Germany

Requests for reprints: Sandra E. Dunn, Departments of Pediatrics, Medical Genetics, and Experimental Medicine, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. Phone: 604-875-2000, ext. 6015; Fax: 604-875-3120; E-mail: sedunn{at}interchange.ubc.ca.

The overexpression of the epidermal growth factor receptor (EGFR) and HER-2 underpin the growth of aggressive breast cancer; still, it is unclear what governs the regulation of these receptors. Our laboratories recently determined that the Y-box binding protein-1 (YB-1), an oncogenic transcription/translation factor, induced breast tumor cell growth in monolayer and in soft agar. Importantly, mutating YB-1 at Ser¹⁰², which resides in the DNA-binding domain, prevented growth induction. We reasoned that the underlying cause for growth attenuation by YB-1(Ser¹⁰²) is through the regulation of EGFR and/or HER-2. The initial link between YB-1 and these receptors was sought by screening primary tumor tissue microarrays. We determined that YB-1 (n = 389 cases) was positively associated with EGFR (P < 0.001, r = 0.213), HER-2 (P = 0.008, r = 0.157), and Ki67 (P < 0.0002, r = 0.219). It was inversely linked to the estrogen receptor (P < 0.001, r = –0.291). Overexpression of YB-1 in a breast cancer cell line increased HER-2 and EGFR. Alternatively, mutation of YB-1 at Ser¹⁰² > Ala¹⁰² prevented the induction of these receptors and rendered the cells less responsive to EGF. The mutant YB-1 protein was also unable to optimally bind to the EGFR and HER-2 promoters based on chromatin immunoprecipitation. Furthermore, knocking down YB-1 with small interfering RNA suppressed the expression of EGFR and HER-2. This was coupled with a decrease in tumor cell growth. In conclusion, YB-1(Ser¹⁰²) is a point of molecular vulnerability for maintaining the expression of EGFR and HER-2. Targeting YB-1 or more specifically YB-1(Ser¹⁰²) are novel approaches to inhibiting the expression of these receptors to ultimately suppress tumor cell growth. (Cancer Res 2006; 66(9): 4872-9)

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