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Clin Cancer Res. 2008 Jul 15;14(14):4427-36. doi: 10.1158/1078-0432.CCR-08-0458.

Anti-invasive and antimetastatic activities of ribosomal protein S6 kinase 4 in breast cancer cells.

Author information

1
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.

Abstract

PURPOSE:

We have previously shown that p90 ribosomal protein S6 kinase 4 (RSK4), an X-linked gene, is highly up-regulated in mammary tumors of MMTV-c-Myc transgenic mice. In this study, we further investigated whether RSK4 inhibits or promotes breast tumor growth and progression.

EXPERIMENTAL DESIGN:

Stable overexpression or small interfering RNA-mediated knockdown of RSK4 was done in the MDA-MB-231 cell line. Stable clones were tested for cell proliferation, anchorage-independent growth in soft agar, invasive and metastatic ability of these clones in vitro and tumorigenesis, invasive and metastatic ability in vivo in severe combined immunodeficient mice.

RESULTS:

Here, we show that exogenous expression of RSK4 resulted in decreased cell proliferation and increased accumulation of cells in G(0)-G(1) phase, which paralleled with enhanced expression of tumor suppressor genes: retinoblastoma protein, retinobl astoma-associated 46 kDa protein, and p21 protein. Overexpression of RSK4 resulted in reduced colony formation in soft agar and suppressed invasive and migratory activities of MDA-MB-231 cells both in vitro and in vivo. Importantly, RSK4-overexpressing cells showed up-regulation of claudin-2 and down-regulation of CXCR4, both of these play roles in invasion and chemotaxis.

CONCLUSIONS:

These results indicate that RSK4 expression may limit the oncogenic, invasive, and metastatic potential of breast cancer cells. Anti-invasive and antimetastatic activities of RSK4 may be, in part, due to its regulation of claudin-2. Increased expression of RSK4 in c-Myc-overexpressing cells and a dose-dependent induction of luciferase reporter gene activity suggest that c-Myc may regulate RSK4 expression.

PMID:
18628456
PMCID:
PMC3771666
DOI:
10.1158/1078-0432.CCR-08-0458
[Indexed for MEDLINE]
Free PMC Article

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