# Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer **Authors:** Heather Karner, Tabea C. Mittmann, Vicky W. Chen, Ashir A. Borah, Andreas Langen, Hassan Yousefi, Lisa Fish, Balyn W. Zaro, Albertas Navickas, Hani Goodarzi PMC · DOI: 10.1126/sciadv.aea9061 · 2026-03-11 ## TL;DR This study reveals how mRNA stability, controlled by specific proteins like RBMS3, suppresses breast cancer metastasis through a newly identified regulatory mechanism. ## Contribution The study introduces GreyHound, a deep-learning model that identifies posttranscriptional regulators of mRNA stability linked to metastasis suppression in breast cancer. ## Key findings - GreyHound identified RBMS3 and TXNIP as key regulators of mRNA stability in breast cancer. - RBMS3 depletion increases metastatic potential and is associated with poor clinical outcomes. - RBMS3-mediated regulation of TXNIP mRNA stability suppresses cancer metastasis in vivo. ## Abstract Heterogeneity in cancer gene expression is typically linked to genetic and epigenetic alterations, yet the extent of contribution from posttranscriptional regulation remains unclear. Here, we systematically measured messenger RNA (mRNA) dynamics across diverse breast cancer models, revealing that mRNA stability substantially shapes gene expression variability. To decipher these dynamics, we developed GreyHound, an interpretable multimodal deep-learning framework integrating RNA sequence features and RNA binding protein (RBP) expression. GreyHound identified an extensive network of RBPs and their regulons underlying variations in mRNA stability, including a regulatory axis centered on RBP RBMS3 and redox regulator TXNIP. RBMS3 depletion resulted in targeted transcript destabilization—associated with poor clinical outcomes and enhanced metastatic potential in xenograft models. In vivo epistasis studies confirmed that RBMS3-mediated regulation of TXNIP mRNA stability drives this metastasis-suppressive program. These findings identify a key posttranscriptional mechanism in breast cancer and illustrate how interpretable models of RNA dynamics can uncover regulatory programs in disease. A deep-learning model links RNA stability control to breast cancer metastasis via a key posttranscriptional regulatory mechanism. ## Linked entities - **Genes:** RBMS3 (RNA binding motif single stranded interacting protein 3) [NCBI Gene 27303], TXNIP (thioredoxin interacting protein) [NCBI Gene 10628] - **Proteins:** RENBP (renin binding protein) - **Diseases:** breast cancer (MONDO:0004989) ## Full-text entities - **Genes:** Rbms3 (RNA binding motif, single stranded interacting protein) [NCBI Gene 207181] {aka 6720477E09Rik, 8430436O14Rik}, PRRX1 (paired related homeobox 1) [NCBI Gene 5396] {aka AGOTC, PHOX1, PMX1, PRX-1, PRX1}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, SLAMF1 (signaling lymphocytic activation molecule family member 1) [NCBI Gene 6504] {aka CD150, CDw150, IPO3, SLAM}, Zim3 (zinc finger, imprinted 3) [NCBI Gene 116811] {aka 1700128I23Rik}, TXNIP (thioredoxin interacting protein) [NCBI Gene 10628] {aka ARRDC6, EST01027, HHCPA78, THIF, VDUP1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, RBM4B (RNA binding motif protein 4B) [NCBI Gene 83759] {aka RBM30, RBM4L, ZCCHC15, ZCCHC21B, ZCRB3B}, HPRT1 (hypoxanthine phosphoribosyltransferase 1) [NCBI Gene 3251] {aka HGPRT, HPRT}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, RBMS3 (RNA binding motif single stranded interacting protein 3) [NCBI Gene 27303], RNASE1 (ribonuclease A family member 1, pancreatic) [NCBI Gene 6035] {aka RAC1, RIB1, RNS1}, BRCA1 (BRCA1 DNA repair associated) [NCBI Gene 672] {aka BRCAI, BRCC1, BROVCA1, FANCS, IRIS, PNCA4}, DNASE1 (deoxyribonuclease 1) [NCBI Gene 1773] {aka DNL1, DRNI}, LGR5 (leucine rich repeat containing G protein-coupled receptor 5) [NCBI Gene 8549] {aka FEX, GPR49, GPR67, GRP49, HG38}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, SAMD4B (sterile alpha motif domain containing 4B) [NCBI Gene 55095] {aka SMGB, Smaug2}, Txnip (thioredoxin interacting protein) [NCBI Gene 56338] {aka 1200008J08Rik, Hyplip1, THIF, Tbp-2, VDUP1}, RBP4 (retinol binding protein 4) [NCBI Gene 5950] {aka MCOPCB10, RDCCAS} - **Diseases:** CIMS (MESH:D009371), diabetic (MESH:D003920), Cancer (MESH:D009369), metastatic (MESH:D000092182), NOD (MESH:D020191), basal breast cancers (MESH:D001943), triple-negative breast cancer (MESH:D064726), metastasis (MESH:D009362) - **Chemicals:** DTT (MESH:D004229), SDS (MESH:D012967), ethanol (MESH:D000431), Water (MESH:D014867), 4-thiouridine (MESH:D013891), TRIzol (MESH:C411644), Iodoacetamide (MESH:D007460), IGEPAL CA-630 (MESH:C010615), EDTA (MESH:D004492), bis-tris (MESH:C026272), streptomycin (MESH:D013307), MgCl2 (MESH:D015636), TE (MESH:D013691), methanol (MESH:D000432), Trypan Blue (MESH:D014343), NaCl (MESH:D012965), sodium deoxycholate (MESH:D003840), Formic Acid (MESH:C030544), salt (MESH:D012492), eosin (MESH:D004801), tween-20 (MESH:D011136), polyethylene terephthalate (MESH:D011093), Mg++ (MESH:D008274), ice (MESH:D007053), BA (MESH:D001464), polyA (MESH:D011061), Ca++ (MESH:D002118), adenosine triphosphate (MESH:D000255), dinucleotide (MESH:D015226), CO2 (MESH:D002245), luciferin (MESH:D000090562), polybrene (MESH:D006583), Agarose (MESH:D012685), MOPS (MESH:C008550), amphotericin B (MESH:D000666), thiol (MESH:D013438), d(T) (MESH:D013936), MeCN (-), crystal violet (MESH:D005840), puromycin (MESH:D011691), glycerol (MESH:D005990), penicillin (MESH:D010406), Hematoxylin (MESH:D006416) - **Species:** Mycoplasma (genus) [taxon 2093], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** R0739S, R0585S, C to T, E2621S, T2A, R0113S, A to C, T to C, C to E, R0547S - **Cell lines:** MCF7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), HEK — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_M624), MDA-LM2 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_5998), CRL-3216 — Homo sapiens (Human), Turner syndrome, Transformed cell line (CVCL_9M67), ZR-75-1 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0588), 293T — Homo sapiens (Human), Transformed cell line (CVCL_0063), HCC1806 — Homo sapiens (Human), Breast acantholytic squamous cell carcinoma, Cancer cell line (CVCL_1258), HTB-131 — Mus musculus (Mouse), Hybridoma (CVCL_A8FQ), HCC38 — Homo sapiens (Human), Breast ductal carcinoma, Cancer cell line (CVCL_1267), CRL-2314 — Homo sapiens (Human), Farber lipogranulomatosis, Finite cell line (CVCL_8A64), MDA — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_4747), -1500 — Homo sapiens (Human), Transformed cell line (CVCL_D870), MDA-MB-453 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0418), MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062) ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12978252/full.md --- Source: https://tomesphere.com/paper/PMC12978252