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RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA

Abstract

The epithelial-to-mesenchymal transition (EMT) has been recognized as a driving force for tumor progression in breast cancer. Recently, our group identified the RNA Binding Motif Single Stranded Interacting Protein 3 (RBMS3) to be significantly associated with an EMT transcriptional program in breast cancer. Additional expression profiling demonstrated that RBMS3 was consistently upregulated by multiple EMT transcription factors and correlated with mesenchymal gene expression in breast cancer cell lines. Functionally, RBMS3 was sufficient to induce EMT in two immortalized mammary epithelial cell lines. In triple-negative breast cancer (TNBC) models, RBMS3 was necessary for maintaining the mesenchymal phenotype and invasion and migration in vitro. Loss of RBMS3 significantly impaired both tumor progression and spontaneous metastasis in vivo. Using a genome-wide approach to interrogate mRNA stability, we found that ectopic expression of RBMS3 upregulates many genes that are resistant to degradation following transcriptional blockade by actinomycin D (ACTD). Specifically, RBMS3 was shown to interact with the mRNA of EMT transcription factor PRRX1 and promote PRRX1 mRNA stability. PRRX1 is required for RBMS3-mediated EMT and is partially sufficient to rescue the effect of RBMS3 knockdown in TNBC cell lines. Together, this study identifies RBMS3 as a novel and common effector of EMT, which could be a promising therapeutic target for TNBC treatment.

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Fig. 1: RBMS3 is commonly upregulated during EMT and associated with EMT-like gene expression in breast cancer cells.
Fig. 2: RBMS3 induces EMT and maintains mesenchymal differentiation.
Fig. 3: RBMS3 is required for mesenchymal gene expression and cell migration/invasion in TNBC.
Fig. 4: RBMS3 is required for tumor progression and spontaneous metastasis in vivo.
Fig. 5: RBMS3 regulates the expression and stability of PRRX1 mRNA.
Fig. 6: PRRX1 is a critical effector of RBMS3-mediated EMT and cell motility in human mammary epithelial cells.
Fig. 7: PRRX1 plays a vital role in RBMS3-mediated EMT and motility in TNBC cells.
Fig. 8: The RBMS3 working model.

Data availability

Microarray data that support the funding of this study have been deposited in the GEO under accession number GSE181322. RNA-seq data that support the finding of this study have been deposited in the GEO under accession number GSE181237.

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Acknowledgements

The authors would like to thank Dr. Larry Matherly at the Karmanos Cancer Institute (KCI) and Wayne State University School of Medicine for helpful discussions and valuable comments. We also want to thank Dr. Robert A. Weinberg at MIT for providing the HMLE cell line.

Funding

This work is supported by Grant boost from Wayne State University (GW) and KCI strategic plan cancer immunology and immunotherapy award (GW and HG). The Biostatistics Core, AMTEC and the Biobanking and Correlative Sciences Core of KCI are supported by grant number P30-CA022453-38.

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Conception and design: CJ B, HG, and GW. Data acquisition: CJB, GW, AVM, LW, JG, and LP. Data analyses and interpretation: CJB, GW, JG, DC, WC, GD, DD, MR, and HG. Drafting of manuscript: CJB and GW. Approval of final manuscript: CJB and GW.

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Correspondence to Guojun Wu.

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Block, C.J., Mitchell, A.V., Wu, L. et al. RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA. Oncogene (2021). https://doi.org/10.1038/s41388-021-02030-x

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