Despite advances in the treatment of breast cancer, disease recurrence rates remain high and secondary tumors are often incurable. The concept of tumor-initiating cells (TICs) is an emerging model to explain cancer relapse. Breast TICs express CD44+/CD24- surface markers, have the capacity to self-renew, differentiate and indefinitely perpetuate tumor initiation1. Recently, a link between epithelial-mesenchymal transition (EMT) and stemness has also been identified2. Due to their inherent resistance to conventional chemotherapeutics, TICs survive and can go on to drive relapse3.
Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor consistently associated with disease recurrence in breast cancer. YB-1 is activated predominantly by phosphorylation via p90 ribosomal S6 kinase (RSK)4. Once activated it up-regulates expression of CD445. YB-1 is expressed in ~70% of one of the most aggressive subtypes – triple-negative breast cancer (TNBC). Currently, the treatment for TNBC relies upon conventional chemotherapies and although these tumors often initially respond well, they paradoxically have the highest relapse rates.
We observe that residual cells after paclitaxel or epirubicin treatment have increased P-RSKS221/7, P-YB-1S102 and CD44 and retain the ability to form mammospheres. Moreover, cells expressing high levels of P-YB-1S102 proliferate in the presence of paclitaxel. Inhibiting YB-1 in residual cells using siRNA suppresses their growth and induces apoptosis. Cell death can also be induced in CD44+/CD24--sorted cells by inhibiting YB-1 directly, or by blocking its activation through RSK inhibition (siRNA or small molecule BI-D1870). The dependence of TICs on YB-1 may be, in part, through regulation of Notch4 as the latter maintains mammary stem cells. Inhibiting YB-1 decreases Notch4 mRNA, which may affect TIC self-renewal. Conversely, expressing constitutively active YB-1S102D increases Notch4. Interestingly, inhibiting RSK in post-EMT MDA-MB-231 cells blocks Notch4 expression, reduces spindle-like morphology and induces E-cadherin re-expression.
Collectively, these data indicate that RSK/YB-1 signaling is critical for the survival of TICs and that inhibiting this pathway has the potential to reduce relapse in TNBC.