To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2614
EMT leads to Metastasis, Breast Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|DNA damage and mutations leading to Metastatic Breast Cancer||adjacent||High||High||Usha Adiga (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Adult, reproductively mature||Moderate|
Key Event Relationship Description
Upstream event: Increased, EMT
Downstream event: Metastasis
Evidence Supporting this KER
The “epithelial–mesenchymal transition” (EMT), a key developmental regulatory program, has been reported to play critical and intricate roles in promoting tumor invasion and metastasis in epithelium-derived carcinomas in recent years. The EMT program allows stationary and polarized epithelial cells, which are connected laterally via several types of junctions and normally interact with the basement membrane via their basal surfaces to maintain apical–basal polarity, to undergo multiple biochemical changes that enable them to disrupt cell–cell adherence, lose apical–basal polarity, dramatically remodel the cytoskeleton, and acquire mesenchymal characteristics such as enhanced migratory capacity, invasiveness, elevated resistance to apoptosis and greatly increased production of ECM components. (Boyer et al., 1993).Some of the cells undergoing EMT have the characteristics of cancer stem cells (CSCs), which are linked to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).Cancer metastasis and cancer therapeutic resistance are linked to the EMT phenomenon (Smith & Bhowmick, 2016; Tanabe, 2013). EMT causes the cell to escape from the basement membrane and metastasize by increasing the production of enzymes that breakdown extracellular matrix components and decreasing adherence to the basement membrane (Smith & Bhowmick, 2016). Therapy resistance is linked to morphological alterations seen during EMT (Smith & Bhowmick, 2016).
EMT is marked by a decrease in E-cadherin and β- -catenin expression and an increase in vimentin, fibronectin, and N-cadherin expression (Irani et al., 2018). EMT is a master mechanism in cancer cells that allows them to lose their epithelial characteristics and gain mesenchymal-like qualities. EMT is the most crucial step in initiating metastasis, including metastasis to lymph nodes, because tumour cell movement is a pre-requisite for the metastatic process (Da et al., 2017). Multiple signalling pathways cause cancer cells to lose their cell-to-cell connections and cellular polarity during EMT, increasing their motility and invasive ness (Huang et al., 2017). MMPs cause E-cadherin to be cleaved, which increases tumour cell motility and invasion (Pradella et al., 2017).
Invasiveness and medication resistance are linked to the morphological and physiological changes associated with EMT (Shibue & Weinberg, 2017). In initial tumours, EMT-activated carcinoma cells penetrate the surrounding stroma (Shibue & Weinberg, 2017). EMT-activated carcinoma cells interact with the extracellular matrix protein to activate focal adhesion kinase and extracellular signal-related kinase, followed by TGFbeta and canonical and/or noncanonical Wnt pathways to develop cancer stem cell (CSC) traits, which contribute to drug resistance (Shibue & Weinberg, 2017).
Drug efflux and cell proliferation are slowed by EMT-associated downregulation of several apoptotic signalling pathways, resulting in general resistance of carcinoma cells to anti-cancer drugs (Shibue & Weinberg, 2017).Snail, an EMT-related transcription factor, promotes the production of the AXL receptor tyrosine kinase, which allows cancer cells to survive by activating AXL signalling when its ligand, growth arrest-specific protein 6 (GAS6), binds to it (Shibue & Weinberg, 2017).
EMT-activated cells are resistant to the deadly effects of cytotoxic T cells, which include increased expression of programmed cell death 1 ligand (PD-L1), which binds to the inhibitory immune-checkpoint receptor programmed cell death protein 1 (PD-1) on the cell surface of cytotoxic T cells(Shibue & Weinberg, 2017).
The reversing process of EMT, which names as a mesenchymal-epithelial transition (MET), maybe one of the candidates for the anti-cancer therapy, where the plasticity of the cell phenotype is of importance and under investigation (Shibue & Weinberg, 2017).
Uncertainties and Inconsistencies
Whenever cell phenotype plasticity is crucial and under investigation, the reverse of EMT, known as the mesenchymal-epithelial transition (MET), may be one of the prospects for anti-cancer therapy (Shibue & Weinberg, 2017).
TGFbeta and Twist induce EMT by upregulating the expression of EMT markers such Snail, Vimentin, N-cadherin, and ABC transporters like ABCA3, ABCC1, ABCC3, and ABCC10 (Saxena et al., 2011).In the treatment with about 0.3, 3, 30 mM of doxorubicin, human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrate increased cell viability compared to control HMLE, dose-dependently (Saxena et al., 2011).
When Twist/FOXC2/Snail overexpressed HMLE is treated with doxorubicin for 48 hours, cell viability increases compared to control HMLE (Saxena et al., 2011).When Twist or Zeb1 were inhibited with small interference RNA (siRNA), cell viability was reduced relative to control MDAMB231 cells treated with doxorubicin for 48 hours (Saxena et al., 2011).
Known modulating factors
In EMT-activated cells, ABC transporters linked to drug resistance are overexpressed (Saxena et al., 2011). In EMT-activated cells, the expression of PD-L1, which binds to PD-1 on cytotoxic T cells, is upregulated, inhibiting cancer immunity and increasing resistance to cancer therapy (Shibue & Weinberg, 2017).
Known Feedforward/Feedback loops influencing this KER
- Understanding the association between EMT and cancer malignancy necessitates further research into the EMT-cancer stem cells (CSC) relationship. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSCs, resulting in tumorigenic potential renewal (Marjanovic, Weinberg, & Chaffer, 2013; Shibue & Weinberg, 2017).The plastic CSC theory demonstrates bidirectional conversions between non-CSCs and CSCs, which could help EMT-activated cells acquire cancer malignancy (Marjanovic et al., 2013).
- Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. Kong et al reported a novel lncRNA, LINC01133 that was downregulated by TGF- β, which could inhibit epithelial–mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC) cells (Kong et al.,2016). SRSF6, an alternative splicing factor that interacts directly with LINC01133, was found to enhance EMT and metastasis in CRC cells even when LINC01133 was not present. The study also found that the EMT process in CRC cells was regulated by LINC01133 in the presence of SRSF6. In vivo, the ability of LINC01133 to prevent metastasis was confirmed. Furthermore, clinical data revealed that LINC01133 expression was favourably correlated with E-cadherin and negatively correlated with Vimentin, and that low LIINC01133 expression in tumours was associated with poor CRC survival. These findings show that LINC01133, by directly binding to SRSF6 as a target mimic and inhibiting EMT and metastasis, could be used as a predictive biomarker and an effective target for anti-metastasis therapy in CRC.
- MiR-148a inhibited Met expression directly by binding to its 30-UTR, according to Zhang et al's findings. Furthermore, reintroducing miR-148a reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT, by inhibiting Met's downstream signalling, such as activating phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3b-Ser9 (Zhang et al.,2015). MiR-148a, when combined, may suppress hepatoma cell EMT and metastasis by adversely regulating Met/Snail signalling.
Domain of Applicability
- BOYER, B., & THIERY, J. P. (1993). Epithelium‐mesenchyme interconversion as example of epithelial plasticity. Apmis, 101(1‐6), 257-268.
Chen, S. P., Liu, B. X., Xu, J., Pei, X. F., Liao, Y. J., Yuan, F., & Zheng, F. (2015). MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC cancer, 15(1), 1-13.
- Cui, B., Zhang, S., Chen, L., Yu, J., Widhopf, G. F., Fecteau, J. F., ... & Kipps, T. J. (2013). Targeting ROR1 inhibits epithelial–mesenchymal transition and metastasis. Cancer research, 73(12), 3649-3660.
Chen, Y., Wang, D. D., Wu, Y. P., Su, D., Zhou, T. Y., Gai, R. H., ... & Yang, B. (2017). MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. British journal of cancer, 117(8), 1192-1201..
- Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C. J., & Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer research, 71(1), 245-254.
- Chen, L., Mai, W., Chen, M., Hu, J., Zhuo, Z., Lei, X., ... & Zhang, D. (2017). Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacological research, 123, 130-142.
Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y. H., Byers, L. A., ... & Qin, F. X. F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nature communications, 5(1), 1-12.
Da, C., Wu, K., Yue, C., Bai, P., Wang, R., Wang, G., ... & Hou, P. (2017). N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways. Oncotarget, 8(5), 8131.
Du, B., & Shim, J. S. (2016). Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules, 21(7), 965.
- Gao, J., Yang, Y., Qiu, R., Zhang, K., Teng, X., Liu, R., & Wang, Y. (2018). Proteomic analysis of the OGT interactome: novel links to epithelial–mesenchymal transition and metastasis of cervical cancer. Carcinogenesis, 39(10), 1222-1234.
- Gumireddy, K., Li, A., Gimotty, P. A., Klein-Szanto, A. J., Showe, L. C., Katsaros, D., ... & Huang, Q. (2009). KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nature cell biology, 11(11), 1297-1304.
- Gujral, T. S., Chan, M., Peshkin, L., Sorger, P. K., Kirschner, M. W., & MacBeath, G. (2014). A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell, 159(4), 844-856.
Huang, Y., Zhao, M., Xu, H., Wang, K., Fu, Z., Jiang, Y., & Yao, Z. (2014). RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis. Oncotarget, 5(16), 6734.
- Huang, R., & Zong, X. (2017). Aberrant cancer metabolism in epithelial–mesenchymal transition and cancer metastasis: Mechanisms in cancer progression. Critical reviews in oncology/hematology, 115, 13-22.
- Inukai, T., Inoue, A., Kurosawa, H., Goi, K., Shinjyo, T., Ozawa, K., ... & Look, A. T. (1999). SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Molecular cell, 4(3), 343-352.
- Irani, S., & Dehghan, A. (2018). The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. Journal of International Society of Preventive & Community Dentistry, 8(2), 110.
- Jackstadt, R., Röh, S., Neumann, J., Jung, P., Hoffmann, R., Horst, D., ... & Hermeking, H. (2013). AP4 is a mediator of epithelial–mesenchymal transition and metastasis in colorectal cancer. Journal of Experimental Medicine, 210(7), 1331-1350.
- Kong, J., Sun, W., Li, C., Wan, L., Wang, S., Wu, Y., ... & Lai, M. (2016). Long non-coding RNA LINC01133 inhibits epithelial–mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. Cancer letters, 380(2), 476-484.
- Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer cell, 15(3), 195-206.
- Liang, Y. J., Wang, Q. Y., Zhou, C. X., Yin, Q. Q., He, M., Yu, X. T., ... & Zhao, Q. (2013). MiR-124 targets Slug to regulate epithelial–mesenchymal transition and metastasis of breast cancer. Carcinogenesis, 34(3), 713-722.
- Liu, Y., Wang, G., Yang, Y., Mei, Z., Liang, Z., Cui, A., ... & Cui, L. (2016). Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner. Oncogene, 35(21), 2789-2800.
Liu, M., Xiao, Y., Tang, W., Li, J., Hong, L., Dai, W., ... & Xiang, L. (2020). HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma. Cancer medicine, 9(11), 3932-3943.
Marjanovic, N. D., Weinberg, R. A., & Chaffer, C. L. (2013). Cell plasticity and heterogeneity in cancer. Clinical chemistry, 59(1), 168-179.
- Pirozzi, G., Tirino, V., Camerlingo, R., Franco, R., La Rocca, A., Liguori, E., ... & Rocco, G. (2011). Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PloS one, 6(6), e21548.
- Pradella, D., Naro, C., Sette, C., & Ghigna, C. (2017). EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Molecular cancer, 16(1), 1-19.
- Sarkar, T. R., Battula, V. L., Werden, S. J., Vijay, G. V., Ramirez-Peña, E. Q., Taube, J. H., ... & Mani, S. A. (2015). GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer. Oncogene, 34(23), 2958-2967.
- Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell death & disease, 2(7), e179-e179.
- Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nature reviews Clinical oncology, 14(10), 611-629.
- Shiota, M., Zardan, A., Takeuchi, A., Kumano, M., Beraldi, E., Naito, S., ... & Gleave, M. E. (2012). Clusterin mediates TGF-β–induced epithelial–mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer research, 72(20), 5261-5272.
- Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in metastasis and therapy resistance. Journal of clinical medicine, 5(2), 17.
- Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. World journal of stem cells, 5(3), 61.
- Tanabe, S. (2015). Origin of cells and network information. World journal of stem cells, 7(3), 535.
- Tanabe, S. (2015). Signaling involved in stem cell reprogramming and differentiation. World journal of stem cells, 7(7), 992.
- Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. World journal of stem cells, 7(1), 208.
Wang, L., Tong, X., Zhou, Z., Wang, S., Lei, Z., Zhang, T., ... & Zhang, H. T. (2018). Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer. Molecular cancer, 17(1), 1-18.
Wu, W. S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., & Look, A. T. (2005). Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell, 123(4), 641-653.
- Yu, C. P., Yu, S., Shi, L., Wang, S., Li, Z. X., Wang, Y. H., ... & Liang, J. (2017). FoxM1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by targeting Snai1. Molecular medicine reports, 16(4), 5181-5188.
- Yu, J., Lei, R., Zhuang, X., Li, X., Li, G., Lev, S., ... & Hu, G. (2016). MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nature communications, 7(1), 1-12.
Yue, B., Song, C., Yang, L., Cui, R., Cheng, X., Zhang, Z., & Zhao, G. (2019). METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Molecular cancer, 18(1), 1-15.
- Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell cycle, 14(4), 481-487.
Zhang, J. P., Zeng, C., Xu, L., Gong, J., Fang, J. H., & Zhuang, S. M. (2014). MicroRNA-148a suppresses the epithelial–mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene, 33(31), 4069-4076.
Zhang, W., Shi, X., Peng, Y., Wu, M., Zhang, P., Xie, R., ... & Wang, J. (2015). HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PloS one, 10(6), e0129603.