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Targeting p90 Ribosomal S6 Kinase Eliminates Tumor‐Initiating Cells by Inactivating Y‐Box Binding Protein‐1 in Triple‐Negative Breast Cancers
Author(s) -
Stratford Anna L.,
Reipas Kristen,
Hu Kaiji,
Fotovati Abbas,
Brough Rachel,
Frankum Jessica,
Takhar Mandeep,
Watson Peter,
Ashworth Alan,
Lord Christopher J.,
Lasham Annette,
Print Cristin G.,
Dunn Sandra E.
Publication year - 2012
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1128
Subject(s) - cd44 , biology , cancer research , gene silencing , triple negative breast cancer , microbiology and biotechnology , ribosomal s6 kinase , kinase , breast cancer , cancer , cell , p70 s6 kinase 1 , protein kinase b , phosphorylation , biochemistry , genetics , gene
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

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