# Over-Expressed Twist Associates with Markers of Epithelial Mesenchymal Transition and Predicts Poor Prognosis in Breast Cancers via ERK and Akt Activation **Authors:** Yong-Qu Zhang, Xiao-Long Wei, Yuan-Ke Liang, Wei-Ling Chen, Fan Zhang, Jing-Wen Bai, Si-Qi Qiu, Cai-Wen Du, Wen-He Huang, Guo-Jun Zhang PMC · DOI: 10.1371/journal.pone.0135851 · PLoS ONE · 2015-08-21 ## TL;DR Twist overexpression in breast cancer is linked to aggressive tumor traits and worse outcomes, partly through ERK and Akt pathways. ## Contribution This study shows Twist promotes EMT and poor prognosis in breast cancer via ERK and Akt activation. ## Key findings - Twist expression was found in 54% of breast cancer patients and correlated with poor prognostic markers. - Twist overexpression reduced disease-free survival and increased tumor aggressiveness in breast cancer cells. - Twist drives EMT and tumorigenesis through activation of Akt and ERK pathways. ## Abstract Overexpression of Twist, a highly conserved basic helix-loop-helix transcription factor, is associated with epithelial-mesenchymal transition (EMT) and predicts poor prognosis in various kinds of cancers, including breast cancer. In order to further clarify Twist’s role in breast cancer, we detected Twist expression in breast cancer tissues by immunohistochemistry. Twist expression was observed in 54% (220/408) of breast cancer patients and was positively associated with tumor size, Ki67, VEGF-C and HER2 expression. Conversely, Twist was negatively associated with estrogen receptor (ER), progesterone receptor (PgR) and E-cadherin expression. Patients with Twist expression had a poorer prognosis for 30-month disease free survival (DFS) (82.9%) than patients with negative Twist (92.3%). Overexpression of Twist led to dramatic changes in cellular morphology, proliferation, migratory/invasive capability, and expression of EMT-related biomarkers in breast cancer cells. Moreover, we show that Twist serves as a driver of tumorigenesis, as well as an inducer of EMT, at least in part, through activation of the Akt and extracellular signal-regulated protein kinase (ERK) pathways which are critical for Twist-mediated EMT. Our results demonstrate that Twist expression is an important prognostic factor in breast cancer patients. ## Linked entities - **Genes:** TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291], EREG (epiregulin) [NCBI Gene 2069], PGR (progesterone receptor) [NCBI Gene 5241], shg (shotgun) [NCBI Gene 37386], VEGFC (vascular endothelial growth factor C) [NCBI Gene 7424], ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] - **Proteins:** AKT1 (AKT serine/threonine kinase 1), EPHB2 (EPH receptor B2) - **Diseases:** breast cancer (MONDO:0004989) ## Full-text entities - **Genes:** Erbb2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 13866] {aka Erbb-2, HER-2, HER2, Neu, c-erbB2, c-neu}, CDKN1B (cyclin dependent kinase inhibitor 1B) [NCBI Gene 403429] {aka Kip1, p27, p27Kip1}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, PGR (progesterone receptor) [NCBI Gene 5241] {aka NR3C3, PR}, CDH1 (cadherin 1) [NCBI Gene 442858] {aka Cadherin-1, Uvomorulin}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, Cdh1 (cadherin 1) [NCBI Gene 12550] {aka ARC-1, E-cad, Ecad, L-CAM, UVO, Um}, VEGFC (vascular endothelial growth factor C) [NCBI Gene 7424] {aka Flt4-L, LMPH1D, LMPHM4, VRP}, Vim (vimentin) [NCBI Gene 22352], EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, VIM (vimentin) [NCBI Gene 7431], Vegfc (vascular endothelial growth factor C) [NCBI Gene 22341] {aka VEGF-C}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, IFI27 (interferon alpha inducible protein 27) [NCBI Gene 3429] {aka FAM14D, ISG12, ISG12A, P27}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Esr1 (estrogen receptor 1 (alpha)) [NCBI Gene 13982] {aka ER, ER-alpha, ERa, ERalpha, ESR, Estr}, Actb (actin, beta) [NCBI Gene 11461] {aka Actx, E430023M04Rik, beta-actin}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, VIM (vimentin) [NCBI Gene 477991], Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Twist1 (twist basic helix-loop-helix transcription factor 1) [NCBI Gene 22160] {aka M-Twist, Pde, Ska10, Ska, Twist, bHLHa38}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, Snai1 (snail family zinc finger 1) [NCBI Gene 20613] {aka Sna, Sna1, Snail, Snail1}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 56637] {aka 7330414F15Rik, 8430431H08Rik, GSK-3, GSK-3beta, GSK3}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, CDH2 (cadherin 2) [NCBI Gene 1000] {aka ACOGS, ADHD8, ARVD14, CD325, CDHN, CDw325}, Cdkn1b (cyclin dependent kinase inhibitor 1B) [NCBI Gene 12576] {aka Kip1, p27, p27Kip1}, MAPK3 (mitogen-activated protein kinase 3) [NCBI Gene 5595] {aka ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1} - **Diseases:** gastric carcinoma (MESH:D013274), chronic kidney disease (MESH:D051436), triple negative breast cancers (MESH:D064726), female (MESH:D005831), invasive ductal carcinoma (MESH:D044584), tumorigenesis (MESH:D063646), metastasis (MESH:D009362), Tumor (MESH:D009369), bladder and prostate cancers (MESH:D011471), fibrosis (MESH:D005355), cervical cancer (MESH:D002583), TNM (MESH:D008207), Breast Cancers (MESH:D001943), death (MESH:D003643), (MESH:D018270) - **Chemicals:** Tween 20 (MESH:D011136), LY294002 (MESH:C085911), Lipofectamine 2000 (MESH:C086724), CO2 (MESH:D002245), paraffin (MESH:D010232), bromophenol blue (MESH:D001978), glycerol (MESH:D005990), TBS-T (MESH:C027647), formalin (MESH:D005557), DMEM (-), TRIzol (MESH:C411644), Gentian Violet (MESH:D005840), NaCl (MESH:D012965), 2-mercaptoethanol (MESH:D008623), Taxol (MESH:D017239), doxorubicin (MESH:D004317), cisplatin (MESH:D002945), U0126 (MESH:C113580), G418 (MESH:C010680), SDS (MESH:D012967), polyvinylidene difluoride (MESH:C024865), methanol (MESH:D000432), (MESH:D015820), (MESH:D019394), (MESH:D014408), (MESH:D018719), (MESH:C508053), (MESH:D042582) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062), T47D — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0553), MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), MCF-7-Twist — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_DR99), BT549 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_1092), SKBR3 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0033) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC4546631/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC4546631/full.md ## References 51 references — full list in the complete paper: https://tomesphere.com/paper/PMC4546631/full.md --- Source: https://tomesphere.com/paper/PMC4546631