Abstract
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.
Highlights
The overexpression of the human epidermal growth factor receptor (HER-2) is clearly associated with one of the most aggressive types of breast cancer (1)
We have identified a second factor expressed in aggressive types of breast cancer, the Y-box binding protein-1 (YB-1) that induces growth promoting genes such as her-2, egfr, proliferating nuclear antigen, cyclin A, and cyclin B
To understand the underlying reason for growth suppression in the HER-2 overexpressing models of breast cancer, we show that inhibiting YB-1 in the BT474-m1 (Fig. 1B, right) and Au565 cells decreased HER-2, EGFR, and ERK1/2 signaling, whereas there was no effect on the P-AKTS473 or P-GSK-3hS9 pathway
Summary
The overexpression of the human epidermal growth factor receptor (HER-2) is clearly associated with one of the most aggressive types of breast cancer (1). Inhibiting YB-1 suppressed the growth of six of seven breast cancer cell lines that were either triple negative or had her-2 amplifications. We silenced YB-1 with siRNA in a panel of breast cancer cell lines and cell growth was evaluated 96 hours later using a high content screening (HCS) platform (Fig. 1A, representative images of YB-1 knockdown).
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