# Molecular and Clinicopathological Biomarkers Predicting Brain Metastasis in Triple-Negative Breast Cancer: A Systematic Review **Authors:** Savi Agarwal, Pasha Mehranpour, Anjani Chawla, Carissa Vaish, Simon Han, Isaac Yang, Madhuri Wadehra PMC · DOI: 10.3390/ijms27041909 · International Journal of Molecular Sciences · 2026-02-16 ## TL;DR This review identifies potential biomarkers for predicting brain metastasis in triple-negative breast cancer, aiming to improve early detection and treatment strategies. ## Contribution The study systematically reviews biomarkers for brain metastasis in triple-negative breast cancer, highlighting key areas for future research. ## Key findings - Transcriptomic studies, growth factor receptors, and immune markers were most frequently studied for TNBCBM. - Circulating protein and transcriptomic biomarkers show promise for early detection of brain metastasis. - Further investigation of these biomarkers could enhance risk stratification and therapeutic development. ## Abstract Almost half of patients with triple-negative breast cancer (TNBC) develop brain metastasis (TNBCBM), a marker of poor prognosis. TNBC is a more aggressive breast cancer subtype which lacks ER, PR, and HER2 expression, and thus, exploring predictive biomarkers is crucial to improving TNBCBM outcomes through targeted therapy. To curate these biomarkers, peer-reviewed publications from 2010 to 2025 were extracted from PubMed, Scopus, Embase, Cochrane, and Web of Science if they evaluated clinicopathological biomarkers of TNBCBM. A total of 130 studies (60 clinical and 70 pre-clinical) were included. Publications most often featured transcriptomic studies, growth factor receptors, and immune microenvironment markers with 37, 19, and 17 studies identified, respectively. While TNBC aggressiveness has been linked to metastasis, advancing stage, and poor prognosis, several studies focused on utilizing circulating protein and transcriptomic biomarkers for early detection. While few pathways appeared specifically for TNBCBM, investigating these biomarkers further may allow for improved risk stratification, clinical trial design, patient selection, and therapeutic development. Identification of the most promising biomarkers will pave the way for improved prognosis of the most lethal complications of TNBC. ## Linked entities - **Diseases:** triple-negative breast cancer (MONDO:0005494) ## Full-text entities - **Genes:** PECAM1 (platelet and endothelial cell adhesion molecule 1) [NCBI Gene 5175] {aka CD31, CD31/EndoCAM, GPIIA', PECA1, PECAM-1, endoCAM}, HSP90B1 (heat shock protein 90 beta family member 1) [NCBI Gene 7184] {aka ECGP, GP96, GRP94, HEL-S-125m, HEL35, TRA1}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, MIR211 (microRNA 211) [NCBI Gene 406993] {aka MIRN211, mir-211}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, MET (MET proto-oncogene, receptor tyrosine kinase) [NCBI Gene 4233] {aka AUTS9, DA11, DFNB97, HGFR, RCCP2, c-Met}, KIF4A (kinesin family member 4A) [NCBI Gene 24137] {aka KIF4, KIF4G1, MRX100, TMDI, XLID100}, PDCD1 (programmed cell death 1) [NCBI Gene 5133] {aka ADMIO4, AIMTBS, CD279, PD-1, PD1, SLEB2}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, Erbb2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 13866] {aka Erbb-2, HER-2, HER2, Neu, c-erbB2, c-neu}, PTHLH (parathyroid hormone like hormone) [NCBI Gene 5744] {aka BDE2, HHM, PLP, PTHR, PTHRP}, Hsp90b1 (heat shock protein 90, beta (Grp94), member 1) [NCBI Gene 22027] {aka ERp99, GRP94, TA-3, Targ2, Tra-1, Tra1}, HYAL1 (hyaluronidase 1) [NCBI Gene 3373] {aka HYAL-1, LUCA1, MPS9, NAT6}, ANGPTL4 (angiopoietin like 4) [NCBI Gene 51129] {aka ARP4, FIAF, HARP, HFARP, NL2, PGAR}, KRT7 (keratin 7) [NCBI Gene 3855] {aka CK7, K2C7, K7, SCL}, CD24 (CD24 molecule) [NCBI Gene 100133941] {aka CD24A}, CD276 (CD276 molecule) [NCBI Gene 80381] {aka 4Ig-B7-H3, B7-H3, B7H3, B7RP-2}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, ERBB3 (erb-b2 receptor tyrosine kinase 3) [NCBI Gene 2065] {aka ErbB-3, FERLK, HER3, LCCS2, MDA-BF-1, VSCN1}, GATA3 (GATA binding protein 3) [NCBI Gene 2625] {aka HDR, HDRS}, EREG (epiregulin) [NCBI Gene 2069] {aka EPR, ER, Ep}, TFRC (transferrin receptor) [NCBI Gene 7037] {aka CD71, IMD46, T9, TFR, TFR1, TR}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, SHC4 (SHC adaptor protein 4) [NCBI Gene 399694] {aka RaLP, SHCD}, SOX10 (SRY-box transcription factor 10) [NCBI Gene 6663] {aka DOM, PCWH, SOX-10, WS2E, WS4, WS4C}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, SDC1 (syndecan 1) [NCBI Gene 6382] {aka CD138, SDC, SYND1, syndecan}, ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, ARID1A (AT-rich interaction domain 1A) [NCBI Gene 8289] {aka B120, BAF250, BAF250a, BM029, C1orf4, CSS2}, ADAM8 (ADAM metallopeptidase domain 8) [NCBI Gene 101] {aka CD156, CD156a, MS2}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, EPCAM (epithelial cell adhesion molecule) [NCBI Gene 4072] {aka Ber-Ep4, BerEp4, DIAR5, EGP-2, EGP314, EGP40}, DDX3X (DEAD-box helicase 3 X-linked) [NCBI Gene 1654] {aka CAP-Rf, DBX, DDX14, DDX3, HLP2, MRX102}, ANXA2 (annexin A2) [NCBI Gene 302] {aka ANX2, ANX2L4, CAL1H, HEL-S-270, LIP2, LPC2}, PRKCQ (protein kinase C theta) [NCBI Gene 5588] {aka PRKCT, nPKC-theta}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, BRCA2 (BRCA2 DNA repair associated) [NCBI Gene 675] {aka BRCC2, BROVCA2, FACD, FAD, FAD1, FANCD}, Paqr7 (progestin and adipoQ receptor family member VII) [NCBI Gene 71904] {aka 2310021M12Rik, Mpra, PGLP, mPR, mPR alpha}, MEF2C (myocyte enhancer factor 2C) [NCBI Gene 4208] {aka C5DELq14.3, DEL5q14.3, NEDHSIL}, Pgr (progesterone receptor) [NCBI Gene 18667] {aka 9930019P03Rik, NR3C3, PR, PR-A, PR-B}, MIR623 (microRNA 623) [NCBI Gene 693208] {aka MIRN623, hsa-mir-623}, SHC1 (SHC adaptor protein 1) [NCBI Gene 6464] {aka SHC, SHCA}, MIR637 (microRNA 637) [NCBI Gene 693222] {aka MIRN637, hsa-mir-637}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, SERPINB1 (serpin family B member 1) [NCBI Gene 1992] {aka EI, ELANH2, HEL-S-27, HEL57, LEI, M/NEI}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, Ddx3x (DEAD box helicase 3, X-linked) [NCBI Gene 13205] {aka D1Pas1-rs2, Ddx3, Fin14}, Ar (androgen receptor) [NCBI Gene 11835] {aka Tfm}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, CRYAB (crystallin alpha B) [NCBI Gene 1410] {aka CMD1II, CRYA2, CTPP2, CTRCT16, HEL-S-101, HSPB5} - **Diseases:** central nervous system (CNS) tumors (MESH:D016543), Metastatic lesions (MESH:D000092182), cancer (MESH:D009369), lung cancer (MESH:D008175), OS (MESH:D011475), brain metastasis (MESH:D009362), injury to (MESH:D014947), hypoxia (MESH:D000860), brain metastases (MESH:D001932), TNBC brain metastases (MESH:D064726), hypoxic (MESH:D002534), breast cancer (MESH:D001943), Lymph node metastasis (MESH:D008207), vasogenic edema (MESH:D001929) - **Chemicals:** phosphatidylinositol 3,4,5-trisphosphate (MESH:C060974), trastuzumab (MESH:D000068878), phosphatidylinositol 4,5-bisphosphate (MESH:D019269), heparan sulfate (MESH:D006497), BioRender (-), hyaluronan (MESH:D006820), nicotinamide riboside (MESH:C018613), lipid (MESH:D008055), afatinib (MESH:D000077716) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12940659/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12940659/full.md ## References 169 references — full list in the complete paper: https://tomesphere.com/paper/PMC12940659/full.md --- Source: https://tomesphere.com/paper/PMC12940659