RSK1 promotes murine breast cancer growth and metastasis
Abstract
Introduction. Triple-negative breast cancer (TNBC), representing over 15% of all breast cancers, has a poorer
prognosis than other subtypes. There is no effective targeted treatment available for the TNBC sufferers. Ribosomal S6 kinases (RSKs) have been previously proposed as drug targets for TNBC based on observations that 85% of these tumors express activated RSKs.
Materials and methods. Herein we examined an involvement of RSK1 (p90 ribosomal S6 kinase 1) in a regulation of TNBC growth and metastatic spread in an animal model, which closely imitates human disease. Mice
were inoculated into mammary fat pad with 4T1 cells or their RSK1-depleted variant. We examined tumor
growth and formation of pulmonary metastasis. Boyden chamber, wound healing and soft agarose assays were
performed to evaluate cells invasion, migration and anchorage-independent growth.
Results. We found that RSK1 promoted tumor growth and metastasis in vivo. After 35 days all animals inoculated
with control cells developed tumors while in the group injected with RSK1-negative cells, there were 75%
tumor-bearing mice. Average tumor mass was estimated as 1.16 g and 0.37 g for RSK1-positive vs. -negative
samples, respectively (p < 0.0001). Quantification of the macroscopic pulmonary metastases indicated that mice
with RSK1-negative tumors developed approximately 85% less metastatic foci on the lung surface (p < 0.001).
This has been supported by in vitro data presenting that RSK1 promoted anchorage-independent cell growth
and migration. Moreover, RSK1 knock-down corresponded with decreased expression of cell cycle regulating
proteins, i.e. cyclin D3, CDK6 and CDK4.
Conclusions. We provide evidence that RSK1 supports tumor growth and metastatic spread in vivo as well as
in vitro migration and survival in non-adherent conditions. Further studies of RSK1 involvement in TNBC progression may substantiate our findings, laying the foundations for development of anti-RSK1-based therapeutic
strategies in the management of patients with TNBC.
Keywords: RSK1 knock-downtriple-negative breast cancermetastasisanimal modelin vitrocell cycle regulation
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