Abstract
<div>Abstract<p>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 (<i>her-2</i>) along with its dimerization partner <i>egfr</i> 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 <i>in vitro</i> and <i>in vivo</i>. Inhibiting YB-1 suppressed the growth of six of seven breast cancer cell lines that had amplified <i>her-2</i> or were triple negative. Importantly, targeting YB-1 induced apoptosis in BT474-m1 and Au565 breast cancer cells known to have <i>her-2</i> 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<sup>S727</sup> but not P-STAT3<sup>Y705</sup> or total STAT3. This was accompanied by decreased P-ERK1/2<sup>T202/Y204</sup>, P-mTOR<sup>S2448</sup>, 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]</p></div>
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