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Targeting YB-1 in HER-2 Overexpressing Breast Cancer Cells Induces Apoptosis via the mTOR/STAT3 Pathway and Suppresses Tumor Growth in Mice

¹ Department of Pediatrics and Experimental Medicine, University of British Columbia and ² Terry Fox Research Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; ³ M. D. Anderson Cancer Center, Houston, Texas; and ⁴ China Medical University, Taichung, Taiwan

Requests for reprints: Sandra E. Dunn, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada. Phone: 604-875-2000, ext. 6015; Fax: 604-875-3120; E-mail: sedunn{at}interchange.ubc.ca.

Key Words: YB-1 • STAT3 • HER-2 • basal-like breast cancer • targeted therapy

The Y-box binding protein-1 (YB-1) is a transcription/translation factor that is highly expressed in primary breast tumors where it is consistently associated with poor survival. It induces human epidermal growth factor receptor (her-2) along with its dimerization partner egfr by directly binding to their promoters. In addition to promoting growth by inducing receptor tyrosine kinases, YB-1 also protects cells against apoptosis through mechanisms that have not been fully revealed. Given this, we addressed whether YB-1 might be an eventual therapeutic target for breast cancer by inhibiting it with small interfering RNAs in vitro and in vivo. Inhibiting YB-1 suppressed the growth of six of seven breast cancer cell lines that had amplified her-2 or were triple negative. Importantly, targeting YB-1 induced apoptosis in BT474-m1 and Au565 breast cancer cells known to have her-2 amplifications. The potential role of signal transducers and activators of transcription 3 (STAT3) was pursued to address the underlying mechanism for YB-1–mediated survival. Inhibition of YB-1 decreased P-STAT3^S727 but not P-STAT3^Y705 or total STAT3. This was accompanied by decreased P-ERK1/2^T202/Y204, P-mTOR^S2448, and total mammalian target of rapamycin mTOR. Furthering the role of STAT3 in these cells, we show that knocking it down recapitulated the induction of apoptosis. Alternatively, constitutively active P-STAT3 rescued YB-1–induced apoptosis. Finally, targeting YB-1 with 2 different siRNAs remarkably suppressed tumor cell growth in soft agar by >90% and delayed tumorigenesis in nude mice. We conclude that HER-2 overexpressing as well as triple-negative breast cancer cells are YB-1 dependent, suggesting it may be a good therapeutic target for these exceptionally aggressive tumors. [Cancer Res 2008;68(21):8661–6]

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