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Muscleblind-like 1 suppresses breast cancer metastatic colonization and stabilizes metastasis suppressor transcripts
Lisa Fish1, Nora Pencheva1, Hani Goodarzi1
1Laboratory of Systems Cancer Biology, Rockefeller University, New York, New York 10065, USA.
Abstract:
Post-transcriptional deregulation is a defining feature of metastatic cancer. While many microRNAs have been implicated as regulators of metastatic progression, less is known about the roles and mechanisms of RNA-binding proteins in this process. We identified muscleblind-like 1 (MBNL1), a gene implicated in myotonic dystrophy, as a robust suppressor of multiorgan breast cancer metastasis. MBNL1 binds the 3' untranslated regions (UTRs) of DBNL (drebrin-like protein) and TACC1 (transforming acidic coiled-coil containing protein 1)-two genes that we implicate as metastasis suppressors. By enhancing the stability of these genes' transcripts, MBNL1 suppresses cell invasiveness. Consistent with these findings, elevated MBNL1 expression in human breast tumors is associated with reduced metastatic relapse likelihood. Our findings delineate a post-transcriptional network that governs breast cancer metastasis through RNA-binding protein-mediated transcript stabilization.
Insights
Muscleblind-like 1 (MBNL1) suppresses breast cancer metastasis by stabilizing key gene transcripts. Higher MBNL1 levels in tumors correlate with a lower risk of metastatic relapse, revealing a new therapeutic target.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Research
Background:
- Post-transcriptional regulation is crucial in metastatic cancer progression.
- While microRNAs are studied, RNA-binding proteins' roles in metastasis are less understood.
Purpose of the Study:
- To identify RNA-binding proteins that regulate breast cancer metastasis.
- To elucidate the mechanism by which MBNL1 suppresses metastasis.
Main Methods:
- Identified muscleblind-like 1 (MBNL1) as a metastasis suppressor.
- Investigated MBNL1 binding to 3' UTRs of DBNL and TACC1 transcripts.
- Assessed MBNL1's effect on transcript stability and cell invasiveness.
- Correlated MBNL1 expression with clinical data from breast cancer patients.
Main Results:
- MBNL1 suppresses multiorgan breast cancer metastasis.
- MBNL1 binds to DBNL and TACC1 3' UTRs, enhancing their transcript stability.
- Enhanced MBNL1-mediated transcript stabilization reduces cancer cell invasiveness.
- Elevated MBNL1 expression in human breast tumors is linked to reduced metastatic relapse.
Conclusions:
- MBNL1 acts as a metastasis suppressor in breast cancer.
- A post-transcriptional network involving MBNL1 stabilizes metastasis suppressor transcripts.
- MBNL1-mediated transcript stabilization is a key mechanism controlling breast cancer cell invasiveness and metastasis.
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