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Y‐box binding protein‐1 (YB‐1) is the first reported oncogenic transcription factor to induce the tumor‐initiating cell (TIC) surface marker CD44 in triple‐negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB‐1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs. In support of this idea, injection of MDA‐MB‐231 cells expressing Flag‐YB‐1 into mice increased tumor growth as well as enhanced CD44 expression. Despite enrichment for TICs, these cells were sensitive to RSK inhibition when treated ex vivo with BI‐D1870. Targeting RSK2 with small interfering RNA (siRNA) or small molecule RSK kinase inhibitors (SL0101 and BI‐D1870) blocked TNBC monolayer cell growth by ∼100%. In a diverse panel of breast tumor cell line models RSK2 siRNA predominantly targeted models of TNBC. RSK2 inhibition decreased  CD44  promoter activity, CD44 mRNA, protein expression, and mammosphere formation. CD44 +  cells had higher P‐RSK S221/227 , P‐YB‐1 S102 , and mitotic activity relative to CD44 −  cells. Importantly, RSK2 inhibition specifically suppressed the growth of TICs and triggered cell death. Moreover, silencing RSK2 delayed tumor initiation in mice. In patients, RSK2 mRNA was associated with poor disease‐free survival in a cohort of 244 women with breast cancer that had not received adjuvant treatment, and its expression was highest in the basal‐like breast cancer subtype. Taking this further, we report that P‐RSK S221/227  is present in primary TNBCs and correlates with P‐YB‐1 S102  as well as CD44. In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs. S TEM  C ELLS  2012;30:1338–1348

Targeting p90 Ribosomal S6 Kinase Eliminates Tumor‐Initiating Cells by Inactivating Y‐Box Binding Protein‐1 in Triple‐Negative Breast Cancers