Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.

Centre for BioSystems Science and Engineering Indian Institute of Science Bangalore 560012 India

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences 612 65 Brno Czech Republic

Department of Experimental Biology Faculty of Science Masaryk University 625 00 Brno Czech Republic

Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY 10065 USA

International Clinical Research Center St Anne's University Hospital 656 91 Brno Czech Republic

Zobrazit více v PubMed

Howlader N., Altekruse S.F., Li C.I., Chen V.W., Clarke C.A., Ries L.A., Cronin K.A. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl. Cancer Inst. 2014;106 doi: 10.1093/jnci/dju055. PubMed DOI PMC

Malorni L., Shetty P.B., De Angelis C., Hilsenbeck S., Rimawi M.F., Elledge R., Osborne C.K., De Placido S., Arpino G. Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up. Breast Cancer Res. Treat. 2012;136:795–804. doi: 10.1007/s10549-012-2315-y. PubMed DOI PMC

Denkert C., Liedtke C., Tutt A., von Minckwitz G. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2017;389:2430–2442. doi: 10.1016/S0140-6736(16)32454-0. PubMed DOI

Dent R., Trudeau M., Pritchard K.I., Hanna W.M., Kahn H.K., Sawka C.A., Lickley L.A., Rawlinson E., Sun P., Narod S.A. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin. Cancer Res. 2007;13:4429–4434. doi: 10.1158/1078-0432.CCR-06-3045. PubMed DOI

Foulkes W.D., Smith I.E., Reis-Filho J.S. Triple-negative breast cancer. N. Engl. J. Med. 2010;363:1938–1948. doi: 10.1056/NEJMra1001389. PubMed DOI

Kassam F., Enright K., Dent R., Dranitsaris G., Myers J., Flynn C., Fralick M., Kumar R., Clemons M. Survival outcomes for patients with metastatic triple-negative breast cancer: Implications for clinical practice and trial design. Clin. Breast Cancer. 2009;9:29–33. doi: 10.3816/CBC.2009.n.005. PubMed DOI

Bertucci F., Finetti P., Cervera N., Esterni B., Hermitte F., Viens P., Birnbaum D. How basal are triple-negative breast cancers? Int. J. Cancer. 2008;123:236–240. doi: 10.1002/ijc.23518. PubMed DOI

Koboldt D.C.F., Fulton R., McLellan M.D., Schmidt H., Kalicki-Veizer J., McMichael J.F., Fulton L.L., Dooling D.J., Ding L., Mardis E.R., et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. doi: 10.1038/nature11412. PubMed DOI PMC

Lehmann B.D., Jovanovic B., Chen X., Estrada M.V., Johnson K.N., Shyr Y., Moses H.L., Sanders M.E., Pietenpol J.A. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS ONE. 2016;11:e0157368. doi: 10.1371/journal.pone.0157368. PubMed DOI PMC

Garrido-Castro A.C., Lin N.U., Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019;9:176–198. doi: 10.1158/2159-8290.CD-18-1177. PubMed DOI PMC

Quail D.F., Joyce J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013;19:1423–1437. doi: 10.1038/nm.3394. PubMed DOI PMC

Janiszewska M., Tabassum D.P., Castano Z., Cristea S., Yamamoto K.N., Kingston N.L., Murphy K.C., Shu S., Harper N.W., Del Alcazar C.G., et al. Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments. Nat. Cell Biol. 2019;21:879–888. doi: 10.1038/s41556-019-0346-x. PubMed DOI PMC

Keren L., Bosse M., Marquez D., Angoshtari R., Jain S., Varma S., Yang S.R., Kurian A., Van Valen D., West R., et al. A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging. Cell. 2018;174:1373–1387.e1319. doi: 10.1016/j.cell.2018.08.039. PubMed DOI PMC

Kim I.S., Gao Y., Welte T., Wang H., Liu J., Janghorban M., Sheng K., Niu Y., Goldstein A., Zhao N., et al. Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms. Nat. Cell Biol. 2019;21:1113–1126. doi: 10.1038/s41556-019-0373-7. PubMed DOI PMC

Wu S.Z., Roden D.L., Wang C., Holliday H., Harvey K., Cazet A.S., Murphy K.J., Pereira B., Al-Eryani G., Bartonicek N., et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 2020:e104063. doi: 10.15252/embj.2019104063. PubMed DOI PMC

Koren S., Bentires-Alj M. Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy. Mol. Cell. 2015;60:537–546. doi: 10.1016/j.molcel.2015.10.031. PubMed DOI

Marusyk A., Janiszewska M., Polyak K. Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance. Cancer Cell. 2020;37:471–484. doi: 10.1016/j.ccell.2020.03.007. PubMed DOI PMC

Shah S.P., Roth A., Goya R., Oloumi A., Ha G., Zhao Y., Turashvili G., Ding J., Tse K., Haffari G., et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486:395–399. doi: 10.1038/nature10933. PubMed DOI PMC

Nieto M.A., Huang R.Y., Jackson R.A., Thiery J.P. Emt: 2016. Cell. 2016;166:21–45. doi: 10.1016/j.cell.2016.06.028. PubMed DOI

Yang J., Antin P., Berx G., Blanpain C., Brabletz T., Bronner M., Campbell K., Cano A., Casanova J., Christofori G., et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2020;21:341–352. doi: 10.1038/s41580-020-0237-9. PubMed DOI PMC

Chaffer C.L., San Juan B.P., Lim E., Weinberg R.A. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016;35:645–654. doi: 10.1007/s10555-016-9648-7. PubMed DOI

Lambert A.W., Pattabiraman D.R., Weinberg R.A. Emerging Biological Principles of Metastasis. Cell. 2017;168:670–691. doi: 10.1016/j.cell.2016.11.037. PubMed DOI PMC

Brabletz T. To differentiate or not--routes towards metastasis. Nat. Rev. Cancer. 2012;12:425–436. doi: 10.1038/nrc3265. PubMed DOI

Ocana O.H., Corcoles R., Fabra A., Moreno-Bueno G., Acloque H., Vega S., Barrallo-Gimeno A., Cano A., Nieto M.A. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012;22:709–724. doi: 10.1016/j.ccr.2012.10.012. PubMed DOI

Ansieau S., Bastid J., Doreau A., Morel A.P., Bouchet B.P., Thomas C., Fauvet F., Puisieux I., Doglioni C., Piccinin S., et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell. 2008;14:79–89. doi: 10.1016/j.ccr.2008.06.005. PubMed DOI

Gal A., Sjoblom T., Fedorova L., Imreh S., Beug H., Moustakas A. Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene. 2008;27:1218–1230. doi: 10.1038/sj.onc.1210741. PubMed DOI

Mani S.A., Guo W., Liao M.J., Eaton E.N., Ayyanan A., Zhou A.Y., Brooks M., Reinhard F., Zhang C.C., Shipitsin M., et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–715. doi: 10.1016/j.cell.2008.03.027. PubMed DOI PMC

Ye X., Tam W.L., Shibue T., Kaygusuz Y., Reinhardt F., Ng Eaton E., Weinberg R.A. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525:256–260. doi: 10.1038/nature14897. PubMed DOI PMC

Bhatia S., Monkman J., Blick T., Pinto C., Waltham M., Nagaraj S.H., Thompson E.W. Interrogation of Phenotypic Plasticity between Epithelial and Mesenchymal States in Breast Cancer. J. Clin. Med. 2019;8:893. doi: 10.3390/jcm8060893. PubMed DOI PMC

Bierie B., Pierce S.E., Kroeger C., Stover D.G., Pattabiraman D.R., Thiru P., Liu Donaher J., Reinhardt F., Chaffer C.L., Keckesova Z., et al. Integrin-beta4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl. Acad. Sci. USA. 2017;114:E2337–E2346. doi: 10.1073/pnas.1618298114. PubMed DOI PMC

Jolly M.K., Tripathi S.C., Jia D., Mooney S.M., Celiktas M., Hanash S.M., Mani S.A., Pienta K.J., Ben-Jacob E., Levine H. Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget. 2016;7:27067–27084. doi: 10.18632/oncotarget.8166. PubMed DOI PMC

Kroger C., Afeyan A., Mraz J., Eaton E.N., Reinhardt F., Khodor Y.L., Thiru P., Bierie B., Ye X., Burge C.B., et al. Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells. Proc. Natl. Acad. Sci. USA. 2019;116:7353–7362. doi: 10.1073/pnas.1812876116. PubMed DOI PMC

Pastushenko I., Brisebarre A., Sifrim A., Fioramonti M., Revenco T., Boumahdi S., Van Keymeulen A., Brown D., Moers V., Lemaire S., et al. Identification of the tumour transition states occurring during EMT. Nature. 2018;556:463–468. doi: 10.1038/s41586-018-0040-3. PubMed DOI

Zhang J., Tian X.J., Zhang H., Teng Y., Li R., Bai F., Elankumaran S., Xing J. TGF-beta-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops. Sci. Signal. 2014;7:ra91. doi: 10.1126/scisignal.2005304. PubMed DOI

Tripathi S., Chakraborty P., Levine H., Jolly M.K. A mechanism for epithelial-mesenchymal heterogeneity in a population of cancer cells. PLoS Comput. Biol. 2020;16:e1007619. doi: 10.1371/journal.pcbi.1007619. PubMed DOI PMC

Espinosa Fernandez J.R., Eckhardt B.L., Lee J., Lim B., Pearson T., Seitz R.S., Hout D.R., Schweitzer B.L., Nielsen T.J., Lawrence O.R., et al. Identification of triple-negative breast cancer cell lines classified under the same molecular subtype using different molecular characterization techniques: Implications for translational research. PLoS ONE. 2020;15:e0231953. doi: 10.1371/journal.pone.0231953. PubMed DOI PMC

Kao J., Salari K., Bocanegra M., Choi Y.L., Girard L., Gandhi J., Kwei K.A., Hernandez-Boussard T., Wang P., Gazdar A.F., et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS ONE. 2009;4:e6146. doi: 10.1371/journal.pone.0006146. PubMed DOI PMC

Neve R.M., Chin K., Fridlyand J., Yeh J., Baehner F.L., Fevr T., Clark L., Bayani N., Coppe J.P., Tong F., et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10:515–527. doi: 10.1016/j.ccr.2006.10.008. PubMed DOI PMC

Karaayvaz M., Cristea S., Gillespie S.M., Patel A.P., Mylvaganam R., Luo C.C., Specht M.C., Bernstein B.E., Michor F., Ellisen L.W. Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nat. Commun. 2018;9:3588. doi: 10.1038/s41467-018-06052-0. PubMed DOI PMC

Davis R.T., Blake K., Ma D., Gabra M.B.I., Hernandez G.A., Phung A.T., Yang Y., Maurer D., Lefebvre A., Alshetaiwi H., et al. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat. Cell Biol. 2020;22:310–320. doi: 10.1038/s41556-020-0477-0. PubMed DOI

Kim C., Gao R., Sei E., Brandt R., Hartman J., Hatschek T., Crosetto N., Foukakis T., Navin N.E. Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing. Cell. 2018;173:879–893.e813. doi: 10.1016/j.cell.2018.03.041. PubMed DOI PMC

Jackson H.W., Fischer J.R., Zanotelli V.R.T., Ali H.R., Mechera R., Soysal S.D., Moch H., Muenst S., Varga Z., Weber W.P., et al. The single-cell pathology landscape of breast cancer. Nature. 2020;578:615–620. doi: 10.1038/s41586-019-1876-x. PubMed DOI

Wagner J., Rapsomaniki M.A., Chevrier S., Anzeneder T., Langwieder C., Dykgers A., Rees M., Ramaswamy A., Muenst S., Soysal S.D., et al. A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer. Cell. 2019;177:1330–1345 e1318. doi: 10.1016/j.cell.2019.03.005. PubMed DOI PMC

Andre F., Dieci M.V., Dubsky P., Sotiriou C., Curigliano G., Denkert C., Loi S. Molecular pathways: Involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin. Cancer Res. 2013;19:28–33. doi: 10.1158/1078-0432.CCR-11-2701. PubMed DOI

He T.F., Yost S.E., Frankel P.H., Dagis A., Cao Y., Wang R., Rosario A., Tu T.Y., Solomon S., Schmolze D., et al. Multi-panel immunofluorescence analysis of tumor infiltrating lymphocytes in triple negative breast cancer: Evolution of tumor immune profiles and patient prognosis. PLoS ONE. 2020;15:e0229955. doi: 10.1371/journal.pone.0229955. PubMed DOI PMC

Chung W., Eum H.H., Lee H.O., Lee K.M., Lee H.B., Kim K.T., Ryu H.S., Kim S., Lee J.E., Park Y.H., et al. Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer. Nat. Commun. 2017;8:15081. doi: 10.1038/ncomms15081. PubMed DOI PMC

Costa A., Kieffer Y., Scholer-Dahirel A., Pelon F., Bourachot B., Cardon M., Sirven P., Magagna I., Fuhrmann L., Bernard C., et al. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell. 2018;33:463–479e410. doi: 10.1016/j.ccell.2018.01.011. PubMed DOI

Tchou J., Kossenkov A.V., Chang L., Satija C., Herlyn M., Showe L.C., Pure E. Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Med. Genom. 2012;5:39. doi: 10.1186/1755-8794-5-39. PubMed DOI PMC

Kieffer Y., Hocine H.R., Gentric G., Pelon F., Bernard C., Bourachot B., Lameiras S., Albergante L., Bonneau C., Guyard A., et al. Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer. Cancer Discov. 2020;10:1330–1351. doi: 10.1158/2159-8290.CD-19-1384. PubMed DOI

Bareche Y., Venet D., Ignatiadis M., Aftimos P., Piccart M., Rothe F., Sotiriou C. Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Ann. Oncol. 2018;29:895–902. doi: 10.1093/annonc/mdy024. PubMed DOI PMC

Stover D.G., Parsons H.A., Ha G., Freeman S.S., Barry W.T., Guo H., Choudhury A.D., Gydush G., Reed S.C., Rhoades J., et al. Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer. J. Clin. Oncol. 2018;36:543–553. doi: 10.1200/JCO.2017.76.0033. PubMed DOI PMC

Turner N., Lambros M.B., Horlings H.M., Pearson A., Sharpe R., Natrajan R., Geyer F.C., van Kouwenhove M., Kreike B., Mackay A., et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene. 2010;29:2013–2023. doi: 10.1038/onc.2009.489. PubMed DOI PMC

Hicks J., Krasnitz A., Lakshmi B., Navin N.E., Riggs M., Leibu E., Esposito D., Alexander J., Troge J., Grubor V., et al. Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res. 2006;16:1465–1479. doi: 10.1101/gr.5460106. PubMed DOI PMC

Gao R., Davis A., McDonald T.O., Sei E., Shi X., Wang Y., Tsai P.C., Casasent A., Waters J., Zhang H., et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat. Genet. 2016;48:1119–1130. doi: 10.1038/ng.3641. PubMed DOI PMC

Jung H.Y., Fattet L., Yang J. Molecular pathways: Linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin. Cancer Res. 2015;21:962–968. doi: 10.1158/1078-0432.CCR-13-3173. PubMed DOI PMC

Thiery J.P., Acloque H., Huang R.Y., Nieto M.A. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890. doi: 10.1016/j.cell.2009.11.007. PubMed DOI

Lamouille S., Xu J., Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2014;15:178–196. doi: 10.1038/nrm3758. PubMed DOI PMC

Massague J. TGFbeta signalling in context. Nat. Rev. Mol. Cell Biol. 2012;13:616–630. doi: 10.1038/nrm3434. PubMed DOI PMC

Scheel C., Eaton E.N., Li S.H., Chaffer C.L., Reinhardt F., Kah K.J., Bell G., Guo W., Rubin J., Richardson A.L., et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145:926–940. doi: 10.1016/j.cell.2011.04.029. PubMed DOI PMC

Wiercinska E., Naber H.P.H., Pardali E., van der Pluijm G., van Dam H., ten Dijke P. The TGF-beta/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res. Treat. 2011;128:657–666. doi: 10.1007/s10549-010-1147-x. PubMed DOI

Kang Y., He W., Tulley S., Gupta G.P., Serganova I., Chen C.R., Manova-Todorova K., Blasberg R., Gerald W.L., Massague J. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl. Acad. Sci. USA. 2005;102:13909–13914. doi: 10.1073/pnas.0506517102. PubMed DOI PMC

Taylor M.A., Amin J.D., Kirschmann D.A., Schiemann W.P. Lysyl oxidase contributes to mechanotransduction-mediated regulation of transforming growth factor-beta signaling in breast cancer cells. Neoplasia. 2011;13:406–418. doi: 10.1593/neo.101086. PubMed DOI PMC

Padua D., Zhang X.H., Wang Q., Nadal C., Gerald W.L., Gomis R.R., Massague J. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008;133:66–77. doi: 10.1016/j.cell.2008.01.046. PubMed DOI PMC

Stuber T., Monjezi R., Wallstabe L., Kuhnemundt J., Nietzer S.L., Dandekar G., Wockel A., Einsele H., Wischhusen J., Hudecek M. Inhibition of TGF-beta-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer. J. Immunother Cancer. 2020;8 doi: 10.1136/jitc-2020-000676. PubMed DOI PMC

Hanks B.A., Holtzhausen A., Evans K.S., Jamieson R., Gimpel P., Campbell O.M., Hector-Greene M., Sun L., Tewari A., George A., et al. Type III TGF-beta receptor downregulation generates an immunotolerant tumor microenvironment. J. Clin. Investig. 2013;123:3925–3940. doi: 10.1172/JCI65745. PubMed DOI PMC

Katayama H., Tsou P., Kobayashi M., Capello M., Wang H., Esteva F., Disis M.L., Hanash S. A plasma protein derived TGF beta signature is a prognostic indicator in triple negative breast cancer. NPJ Precis. Oncol. 2019;3 doi: 10.1038/s41698-019-0082-5. PubMed DOI PMC

Buijs J.T., Henriquez N.V., Van Overveld P.G.M., Van der Horst G., Que I., Schwaninger R., Rentsch C., Ten Dijke P., Cleton-Jansen A.M., Driouch K., et al. Bone morphogenetic protein 7 in the development and treatment of bone Metastases from breast cancer. Cancer Res. 2007;67:8742–8751. doi: 10.1158/0008-5472.CAN-06-2490. PubMed DOI

Naber H.P., Wiercinska E., Pardali E., van Laar T., Nirmala E., Sundqvist A., van Dam H., van der Horst G., van der Pluijm G., Heckmann B., et al. BMP-7 inhibits TGF-beta-induced invasion of breast cancer cells through inhibition of integrin beta(3) expression. Cell Oncol. 2012;35:19–28. doi: 10.1007/s13402-011-0058-0. PubMed DOI PMC

Parvani J.G., Gujrati M.D., Mack M.A., Schiemann W.P., Lu Z.R. Silencing beta3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple-Negative Breast Cancer. Cancer Res. 2015;75:2316–2325. doi: 10.1158/0008-5472.CAN-14-3485. PubMed DOI PMC

Choi S., Yu J., Park A., Dubon M.J., Do J., Kim Y., Nam D., Noh J., Park K.S. BMP-4 enhances epithelial mesenchymal transition and cancer stem cell properties of breast cancer cells via Notch signaling. Sci. Rep. 2019;9:11724. doi: 10.1038/s41598-019-48190-5. PubMed DOI PMC

Huang P., Chen A., He W., Li Z., Zhang G., Liu Z., Liu G., Liu X., He S., Xiao G., et al. BMP-2 induces EMT and breast cancer stemness through Rb and CD44. Cell Death Discov. 2017;3:17039. doi: 10.1038/cddiscovery.2017.39. PubMed DOI PMC

Dirat B., Bochet L., Dabek M., Daviaud D., Dauvillier S., Majed B., Wang Y.Y., Meulle A., Salles B., Le Gonidec S., et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71:2455–2465. doi: 10.1158/0008-5472.CAN-10-3323. PubMed DOI

D’Esposito V., Liguoro D., Ambrosio M.R., Collina F., Cantile M., Spinelli R., Raciti G.A., Miele C., Valentino R., Campiglia P., et al. Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5. Oncotarget. 2016;7:24495–24509. doi: 10.18632/oncotarget.8336. PubMed DOI PMC

Pinilla S., Alt E., Abdul Khalek F.J., Jotzu C., Muehlberg F., Beckmann C., Song Y.H. Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. Cancer Lett. 2009;284:80–85. doi: 10.1016/j.canlet.2009.04.013. PubMed DOI

Olson O.C., Quail D.F., Joyce J.A. Obesity and the tumor microenvironment. Science. 2017;358:1130–1131. doi: 10.1126/science.aao5801. PubMed DOI

Sabol R.A., Bowles A.C., Cote A., Wise R., O’Donnell B., Matossian M.D., Hossain F.M., Burks H.E., Del Valle L., Miele L., et al. Leptin produced by obesity-altered adipose stem cells promotes metastasis but not tumorigenesis of triple-negative breast cancer in orthotopic xenograft and patient-derived xenograft models. Breast Cancer Res. 2019;21:67. doi: 10.1186/s13058-019-1153-9. PubMed DOI PMC

Gyamfi J., Lee Y.H., Eom M., Choi J. Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci. Rep. 2018;8:8859. doi: 10.1038/s41598-018-27184-9. PubMed DOI PMC

Yu Y., Xiao C.H., Tan L.D., Wang Q.S., Li X.Q., Feng Y.M. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br. J. Cancer. 2014;110:724–732. doi: 10.1038/bjc.2013.768. PubMed DOI PMC

Ren Y., Jia H.H., Xu Y.Q., Zhou X., Zhao X.H., Wang Y.F., Song X., Zhu Z.Y., Sun T., Dou Y., et al. Paracrine and epigenetic control of CAF-induced metastasis: The role of HOTAIR stimulated by TGF-ss1 secretion. Mol. Cancer. 2018;17:5. doi: 10.1186/s12943-018-0758-4. PubMed DOI PMC

Wen S., Hou Y., Fu L., Xi L., Yang D., Zhao M., Qin Y., Sun K., Teng Y., Liu M. Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin beta3-p38 MAPK signalling. Cancer Lett. 2019;442:320–332. doi: 10.1016/j.canlet.2018.10.015. PubMed DOI

El-Haibi C.P., Bell G.W., Zhang J., Collmann A.Y., Wood D., Scherber C.M., Csizmadia E., Mariani O., Zhu C., Campagne A., et al. Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc. Natl. Acad. Sci. USA. 2012;109:17460–17465. doi: 10.1073/pnas.1206653109. PubMed DOI PMC

Zhang W., Xu J., Fang H., Tang L., Chen W., Sun Q., Zhang Q., Yang F., Sun Z., Cao L., et al. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling. FASEB J. 2018;32:276–288. doi: 10.1096/fj.201700237RR. PubMed DOI

Park J., Schwarzbauer J.E. Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene. 2014;33:1649–1657. doi: 10.1038/onc.2013.118. PubMed DOI PMC

Zoltan-Jones A., Huang L., Ghatak S., Toole B.P. Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J. Biol. Chem. 2003;278:45801–45810. doi: 10.1074/jbc.M308168200. PubMed DOI

Louie E., Nik S., Chen J.S., Schmidt M., Song B., Pacson C., Chen X.F., Park S., Ju J., Chen E.I. Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Res. 2010;12:R94. doi: 10.1186/bcr2773. PubMed DOI PMC

Lundgren K., Nordenskjold B., Landberg G. Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer. Br. J. Cancer. 2009;101:1769–1781. doi: 10.1038/sj.bjc.6605369. PubMed DOI PMC

Xing F., Okuda H., Watabe M., Kobayashi A., Pai S.K., Liu W., Pandey P.R., Fukuda K., Hirota S., Sugai T., et al. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene. 2011;30:4075–4086. doi: 10.1038/onc.2011.122. PubMed DOI PMC

Lock F.E., McDonald P.C., Lou Y., Serrano I., Chafe S.C., Ostlund C., Aparicio S., Winum J.Y., Supuran C.T., Dedhar S. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene. 2013;32:5210–5219. doi: 10.1038/onc.2012.550. PubMed DOI

Ciccone V., Filippelli A., Angeli A., Supuran C.T., Morbidelli L. Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness. Int. J. Mol. Sci. 2020;21:2983. doi: 10.3390/ijms21082983. PubMed DOI PMC

Chao Y., Wu Q., Shepard C., Wells A. Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clin. Exp. Metastasis. 2012;29:39–50. doi: 10.1007/s10585-011-9427-3. PubMed DOI PMC

Chao Y.L., Shepard C.R., Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol. Cancer. 2010;9:179. doi: 10.1186/1476-4598-9-179. PubMed DOI PMC

Yang M., Ma B., Shao H., Clark A.M., Wells A. Macrophage phenotypic subtypes diametrically regulate epithelial-mesenchymal plasticity in breast cancer cells. BMC Cancer. 2016;16:419. doi: 10.1186/s12885-016-2411-1. PubMed DOI PMC

Esposito M., Mondal N., Greco T.M., Wei Y., Spadazzi C., Lin S.C., Zheng H., Cheung C., Magnani J.L., Lin S.H., et al. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 2019;21:627–639. doi: 10.1038/s41556-019-0309-2. PubMed DOI PMC

Knutson K.L., Lu H., Stone B., Reiman J.M., Behrens M.D., Prosperi C.M., Gad E.A., Smorlesi A., Disis M.L. Immunoediting of cancers may lead to epithelial to mesenchymal transition. J. Immunol. 2006;177:1526–1533. doi: 10.4049/jimmunol.177.3.1526. PubMed DOI

Park J.H., Jonas S.F., Bataillon G., Criscitiello C., Salgado R., Loi S., Viale G., Lee H.J., Dieci M.V., Kim S.B., et al. Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann. Oncol. 2019;30:1941–1949. doi: 10.1093/annonc/mdz395. PubMed DOI

Disis M.L., Stanton S.E. Triple-negative breast cancer: Immune modulation as the new treatment paradigm. Am. Soc. Clin. Oncol. Educ. Book. 2015:e25–e30. doi: 10.14694/EdBook_AM.2015.35.e25. PubMed DOI

Mahmoud S.M., Paish E.C., Powe D.G., Macmillan R.D., Grainge M.J., Lee A.H., Ellis I.O., Green A.R. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 2011;29:1949–1955. doi: 10.1200/JCO.2010.30.5037. PubMed DOI

Akalay I., Janji B., Hasmim M., Noman M.Z., Andre F., De Cremoux P., Bertheau P., Badoual C., Vielh P., Larsen A.K., et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res. 2013;73:2418–2427. doi: 10.1158/0008-5472.CAN-12-2432. PubMed DOI

Seo A.N., Lee H.J., Kim E.J., Kim H.J., Jang M.H., Lee H.E., Kim Y.J., Kim J.H., Park S.Y. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br. J. Cancer. 2013;109:2705–2713. doi: 10.1038/bjc.2013.634. PubMed DOI PMC

Hsu J.M., Xia W., Hsu Y.H., Chan L.C., Yu W.H., Cha J.H., Chen C.T., Liao H.W., Kuo C.W., Khoo K.H., et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat. Commun. 2018;9:1908. doi: 10.1038/s41467-018-04313-6. PubMed DOI PMC

Taube J.H., Herschkowitz J.I., Komurov K., Zhou A.Y., Gupta S., Yang J., Hartwell K., Onder T.T., Gupta P.B., Evans K.W., et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl. Acad. Sci. USA. 2010;107:15449–15454. doi: 10.1073/pnas.1004900107. PubMed DOI PMC

Stemmler M.P., Eccles R.L., Brabletz S., Brabletz T. Non-redundant functions of EMT transcription factors. Nat. Cell Biol. 2019;21:102–112. doi: 10.1038/s41556-018-0196-y. PubMed DOI

Chaffer C.L., Marjanovic N.D., Lee T., Bell G., Kleer C.G., Reinhardt F., D’Alessio A.C., Young R.A., Weinberg R.A. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013;154:61–74. doi: 10.1016/j.cell.2013.06.005. PubMed DOI PMC

Drapela S., Bouchal J., Jolly M.K., Culig Z., Soucek K. ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance. Front. Mol. Biosci. 2020;7:36. doi: 10.3389/fmolb.2020.00036. PubMed DOI PMC

Karihtala P., Auvinen P., Kauppila S., Haapasaari K.M., Jukkola-Vuorinen A., Soini Y. Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: Association with an aggressive tumour phenotype. Breast Cancer Res. Treat. 2013;138:81–90. doi: 10.1007/s10549-013-2442-0. PubMed DOI

Wu H.T., Zhong H.T., Li G.W., Shen J.X., Ye Q.Q., Zhang M.L., Liu J. Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer. J. Transl. Med. 2020;18:51. doi: 10.1186/s12967-020-02240-z. PubMed DOI PMC

Llorens M.C., Rossi F.A., Garcia I.A., Cooke M., Abba M.C., Lopez-Haber C., Barrio-Real L., Vaglienti M.V., Rossi M., Bocco J.L., et al. PKCalpha Modulates Epithelial-to-Mesenchymal Transition and Invasiveness of Breast Cancer Cells Through ZEB1. Front. Oncol. 2019;9:1323. doi: 10.3389/fonc.2019.01323. PubMed DOI PMC

Cho H.J., Oh N., Park J.H., Kim K.S., Kim H.K., Lee E., Hwang S., Kim S.J., Park K.S. ZEB1 Collaborates with ELK3 to Repress E-Cadherin Expression in Triple-Negative Breast Cancer Cells. Mol. Cancer Res. 2019;17:2257–2266. doi: 10.1158/1541-7786.MCR-19-0380. PubMed DOI

Kong S.Y., Kim K.S., Kim J., Kim M.K., Lee K.H., Lee J.Y., Oh N., Park J.I., Park J.H., Heo S.H., et al. The ELK3-GATA3 axis orchestrates invasion and metastasis of breast cancer cells in vitro and in vivo. Oncotarget. 2016;7:65137–65146. doi: 10.18632/oncotarget.11427. PubMed DOI PMC

Dydensborg A.B., Rose A.A., Wilson B.J., Grote D., Paquet M., Giguere V., Siegel P.M., Bouchard M. GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene. 2009;28:2634–2642. doi: 10.1038/onc.2009.126. PubMed DOI

Chu I.M., Lai W.C., Aprelikova O., El Touny L.H., Kouros-Mehr H., Green J.E. Expression of GATA3 in MDA-MB-231 triple-negative breast cancer cells induces a growth inhibitory response to TGFss. PLoS ONE. 2013;8:e61125. doi: 10.1371/journal.pone.0061125. PubMed DOI PMC

Yan W., Cao Q.J., Arenas R.B., Bentley B., Shao R. GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition. J. Biol. Chem. 2010;285:14042–14051. doi: 10.1074/jbc.M110.105262. PubMed DOI PMC

Chakrabarti R., Hwang J., Andres Blanco M., Wei Y., Lukacisin M., Romano R.A., Smalley K., Liu S., Yang Q., Ibrahim T., et al. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat. Cell Biol. 2012;14:1212–1222. doi: 10.1038/ncb2607. PubMed DOI PMC

Casas E., Kim J., Bendesky A., Ohno-Machado L., Wolfe C.J., Yang J. Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res. 2011;71:245–254. doi: 10.1158/0008-5472.CAN-10-2330. PubMed DOI PMC

Gras B., Jacqueroud L., Wierinckx A., Lamblot C., Fauvet F., Lachuer J., Puisieux A., Ansieau S. Snail family members unequally trigger EMT and thereby differ in their ability to promote the neoplastic transformation of mammary epithelial cells. PLoS ONE. 2014;9:e92254. doi: 10.1371/journal.pone.0092254. PubMed DOI PMC

Subbalakshmi A.R., Sahoo S., Biswas K., Jolly M.K. A Computational Systems Biology Approach Identifies SLUG as a Mediator of Partial Epithelial-Mesenchymal Transition (EMT) Cells Tissues Organs. 2021:1–14. doi: 10.1159/000512520. PubMed DOI

Cantile M., Pettinato G., Procino A., Feliciello I., Cindolo L., Cillo C. In vivo expression of the whole HOX gene network in human breast cancer. Eur. J. Cancer. 2003;39:257–264. doi: 10.1016/S0959-8049(02)00599-3. PubMed DOI

De Bessa Garcia S.A., Araujo M., Pereira T., Mouta J., Freitas R. HOX genes function in Breast Cancer development. Biochim. Biophys. Acta Rev. Cancer. 2020;1873:188358. doi: 10.1016/j.bbcan.2020.188358. PubMed DOI

Li B., Huang Q., Wei G.H. The Role of HOX Transcription Factors in Cancer Predisposition and Progression. Cancers. 2019;11:528. doi: 10.3390/cancers11040528. PubMed DOI PMC

Hayashida T., Takahashi F., Chiba N., Brachtel E., Takahashi M., Godin-Heymann N., Gross K.W., Vivanco M., Wijendran V., Shioda T., et al. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc. Natl. Acad. Sci. USA. 2010;107:1100–1105. doi: 10.1073/pnas.0912710107. PubMed DOI PMC

Gong C., Zou J., Zhang M., Zhang J., Xu S., Zhu S., Yang M., Li D., Wang Y., Shi J., et al. Upregulation of MGP by HOXC8 promotes the proliferation, migration, and EMT processes of triple-negative breast cancer. Mol. Carcinog. 2019;58:1863–1875. doi: 10.1002/mc.23079. PubMed DOI

Yu M., Smolen G.A., Zhang J., Wittner B., Schott B.J., Brachtel E., Ramaswamy S., Maheswaran S., Haber D.A. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev. 2009;23:1737–1742. doi: 10.1101/gad.1809309. PubMed DOI PMC

Cieply B., Riley P.t., Pifer P.M., Widmeyer J., Addison J.B., Ivanov A.V., Denvir J., Frisch S.M. Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2. Cancer Res. 2012;72:2440–2453. doi: 10.1158/0008-5472.CAN-11-4038. PubMed DOI PMC

Mooney S.M., Talebian V., Jolly M.K., Jia D., Gromala M., Levine H., McConkey B.J. The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer. J. Cell Biochem. 2017;118:2559–2570. doi: 10.1002/jcb.25974. PubMed DOI

Werner S., Frey S., Riethdorf S., Schulze C., Alawi M., Kling L., Vafaizadeh V., Sauter G., Terracciano L., Schumacher U., et al. Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer. J. Biol. Chem. 2013;288:22993–23008. doi: 10.1074/jbc.M113.456293. PubMed DOI PMC

Jolly M.K., Somarelli J.A., Sheth M., Biddle A., Tripathi S.C., Armstrong A.J., Hanash S.M., Bapat S.A., Rangarajan A., Levine H. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol. Ther. 2019;194:161–184. doi: 10.1016/j.pharmthera.2018.09.007. PubMed DOI

Vervoort S.J., Lourenco A.R., van Boxtel R., Coffer P.J. SOX4 mediates TGF-beta-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition. PLoS ONE. 2013;8:e53238. doi: 10.1371/journal.pone.0053238. PubMed DOI PMC

Schmidt J.M., Panzilius E., Bartsch H.S., Irmler M., Beckers J., Kari V., Linnemann J.R., Dragoi D., Hirschi B., Kloos U.J., et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 2015;10:131–139. doi: 10.1016/j.celrep.2014.12.032. PubMed DOI

Grosse-Wilde A., Fouquier d’Herouel A., McIntosh E., Ertaylan G., Skupin A., Kuestner R.E., del Sol A., Walters K.A., Huang S. Stemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival. PLoS ONE. 2015;10:e0126522. doi: 10.1371/journal.pone.0126522. PubMed DOI PMC

Grosse-Wilde A., Kuestner R.E., Skelton S.M., MacIntosh E., d′Herouel A.F., Ertaylan G., Del Sol A., Skupin A., Huang S. Loss of inter-cellular cooperation by complete epithelial-mesenchymal transition supports favorable outcomes in basal breast cancer patients. Oncotarget. 2018;9:20018–20033. doi: 10.18632/oncotarget.25034. PubMed DOI PMC

Pastushenko I., Mauri F., Song Y., de Cock F., Meeusen B., Swedlund B., Impens F., Van Haver D., Opitz M., Thery M., et al. Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis. Nature. 2021;589:448–455. doi: 10.1038/s41586-020-03046-1. PubMed DOI PMC

Bushweller J.H. Targeting transcription factors in cancer—From undruggable to reality. Nat. Rev. Cancer. 2019;19:611–624. doi: 10.1038/s41568-019-0196-7. PubMed DOI PMC

Dhawan A., Scott J.G., Harris A.L., Buffa F.M. Pan-cancer characterisation of microRNA across cancer hallmarks reveals microRNA-mediated downregulation of tumour suppressors. Nat. Commun. 2018;9:5228. doi: 10.1038/s41467-018-07657-1. PubMed DOI PMC

Peng Y., Croce C.M. The role of MicroRNAs in human cancer. Signal Transduct. Target Ther. 2016;1:15004. doi: 10.1038/sigtrans.2015.4. PubMed DOI PMC

Gregory P.A., Bert A.G., Paterson E.L., Barry S.C., Tsykin A., Farshid G., Vadas M.A., Khew-Goodall Y., Goodall G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008;10:593–601. doi: 10.1038/ncb1722. PubMed DOI

Hurteau G.J., Carlson J.A., Spivack S.D., Brock G.J. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 2007;67:7972–7976. doi: 10.1158/0008-5472.CAN-07-1058. PubMed DOI

Korpal M., Lee E.S., Hu G., Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 2008;283:14910–14914. doi: 10.1074/jbc.C800074200. PubMed DOI PMC

Pattabiraman D.R., Bierie B., Kober K.I., Thiru P., Krall J.A., Zill C., Reinhardt F., Tam W.L., Weinberg R.A. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science. 2016;351:aad3680. doi: 10.1126/science.aad3680. PubMed DOI PMC

Brabletz S., Brabletz T. The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? EMBO Rep. 2010;11:670–677. doi: 10.1038/embor.2010.117. PubMed DOI PMC

Jolly M.K., Celia-Terrassa T. Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression. J. Clin. Med. 2019;8:1542. doi: 10.3390/jcm8101542. PubMed DOI PMC

Rogers T.J., Christenson J.L., Greene L.I., O’Neill K.I., Williams M.M., Gordon M.A., Nemkov T., D’Alessandro A., Degala G.D., Shin J., et al. Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. Mol. Cancer Res. 2019;17:30–41. doi: 10.1158/1541-7786.MCR-18-0246. PubMed DOI PMC

Tryndyak V.P., Beland F.A., Pogribny I.P. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int. J. Cancer. 2010;126:2575–2583. doi: 10.1002/ijc.24972. PubMed DOI

Wang Q., Cheng Y., Wang Y., Fan Y., Li C., Zhang Y., Dong Q., Ma Y., Teng Y.E., Qu X., et al. Tamoxifen reverses epithelial-mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells. BMC Cancer. 2017;17:492. doi: 10.1186/s12885-017-3457-4. PubMed DOI PMC

Korpal M., Ell B.J., Buffa F.M., Ibrahim T., Blanco M.A., Celia-Terrassa T., Mercatali L., Khan Z., Goodarzi H., Hua Y., et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat. Med. 2011;17:1101–1108. doi: 10.1038/nm.2401. PubMed DOI PMC

Dykxhoorn D.M., Wu Y., Xie H., Yu F., Lal A., Petrocca F., Martinvalet D., Song E., Lim B., Lieberman J. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS ONE. 2009;4:e7181. doi: 10.1371/journal.pone.0007181. PubMed DOI PMC

Chen J., Shin V.Y., Siu M.T., Ho J.C., Cheuk I., Kwong A. miR-199a-5p confers tumor-suppressive role in triple-negative breast cancer. BMC Cancer. 2016;16:887. doi: 10.1186/s12885-016-2916-7. PubMed DOI PMC

Wu J., Li W.Z., Huang M.L., Wei H.L., Wang T., Fan J., Li N.L., Ling R. Regulation of cancerous progression and epithelial-mesenchymal transition by miR-34c-3p via modulation of MAP3K2 signaling in triple-negative breast cancer cells. Biochem. Biophys. Res. Commun. 2017;483:10–16. doi: 10.1016/j.bbrc.2017.01.023. PubMed DOI

Wang J., Li M., Han X., Wang H., Wang X., Ma G., Xia T., Wang S. MiR-1976 knockdown promotes epithelial-mesenchymal transition and cancer stem cell properties inducing triple-negative breast cancer metastasis. Cell Death Dis. 2020;11:500. doi: 10.1038/s41419-020-2711-x. PubMed DOI PMC

Jang M.H., Kim H.J., Gwak J.M., Chung Y.R., Park S.Y. Prognostic value of microRNA-9 and microRNA-155 expression in triple-negative breast cancer. Hum. Pathol. 2017;68:69–78. doi: 10.1016/j.humpath.2017.08.026. PubMed DOI

Jolly M.K., Ware K.E., Gilja S., Somarelli J.A., Levine H. EMT and MET: Necessary or permissive for metastasis? Mol. Oncol. 2017;11:755–769. doi: 10.1002/1878-0261.12083. PubMed DOI PMC

Bukholm I.K., Nesland J.M., Borresen-Dale A.L. Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients. J. Pathol. 2000;190:15–19. doi: 10.1002/(SICI)1096-9896(200001)190:1<15::AID-PATH489>3.0.CO;2-L. PubMed DOI

Kowalski P.J., Rubin M.A., Kleer C.G. E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res. 2003;5:R217–R222. doi: 10.1186/bcr651. PubMed DOI PMC

Park D., Karesen R., Axcrona U., Noren T., Sauer T. Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS Acta Pathol. Microbiol. et Immunol. Scand. 2007;115:52–65. doi: 10.1111/j.1600-0463.2007.apm_524.x. PubMed DOI

Jia W., Deshmukh A., Mani S.A., Jolly M.K., Levine H. A possible role for epigenetic feedback regulation in the dynamics of the epithelial-mesenchymal transition (EMT) Phys. Biol. 2019;16:066004. doi: 10.1088/1478-3975/ab34df. PubMed DOI PMC

Liu X., Li J., Cadilha B.L., Markota A., Voigt C., Huang Z., Lin P.P., Wang D.D., Dai J., Kranz G., et al. Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis. Sci. Adv. 2019;5:eaav4275. doi: 10.1126/sciadv.aav4275. PubMed DOI PMC

Khoo B.L., Lee S.C., Kumar P., Tan T.Z., Warkiani M.E., Ow S.G., Nandi S., Lim C.T., Thiery J.P. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget. 2015;6:15578–15593. doi: 10.18632/oncotarget.3903. PubMed DOI PMC

Yu M., Bardia A., Wittner B.S., Stott S.L., Smas M.E., Ting D.T., Isakoff S.J., Ciciliano J.C., Wells M.N., Shah A.M., et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–584. doi: 10.1126/science.1228522. PubMed DOI PMC

Bocci F., Mandal S., Tejaswi T., Jolly M.K. Investigating epithelial-mesenchymal heterogeneity of tumors and circulating tumor cells with transcriptomic analysis and biophysical modeling. Comput. Syst. Oncol. 2021:e1015. doi: 10.1002/cso2.1015. DOI

Radovich M., Jiang G., Hancock B.A., Chitambar C., Nanda R., Falkson C., Lynce F.C., Gallagher C., Isaacs C., Blaya M., et al. Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial. JAMA Oncol. 2020;6:1410–1415. doi: 10.1001/jamaoncol.2020.2295. PubMed DOI PMC

Gwark S.C., Kim J., Lee C.H., Kim Y.H., Kim M.S., Hong S.W., Choi M.Y., Jeon B.H., Kwon N.J., Kim K.Y., et al. Analysis of the serial circulating tumor cell count during neoadjuvant chemotherapy in breast cancer patients. Sci. Rep. 2020;10:17466. doi: 10.1038/s41598-020-74577-w. PubMed DOI PMC

Peeters D.J., van Dam P.J., Van den Eynden G.G., Rutten A., Wuyts H., Pouillon L., Peeters M., Pauwels P., Van Laere S.J., van Dam P.A., et al. Detection and prognostic significance of circulating tumour cells in patients with metastatic breast cancer according to immunohistochemical subtypes. Br. J. Cancer. 2014;110:375–383. doi: 10.1038/bjc.2013.743. PubMed DOI PMC

Ignatiadis M., Xenidis N., Perraki M., Apostolaki S., Politaki E., Kafousi M., Stathopoulos E.N., Stathopoulou A., Lianidou E., Chlouverakis G., et al. Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J. Clin. Oncol. 2007;25:5194–5202. doi: 10.1200/JCO.2007.11.7762. PubMed DOI

Micalizzi D.S., Haber D.A., Maheswaran S. Cancer metastasis through the prism of epithelial-to-mesenchymal transition in circulating tumor cells. Mol. Oncol. 2017;11:770–780. doi: 10.1002/1878-0261.12081. PubMed DOI PMC

Ramani V.C., Lemaire C.A., Triboulet M., Casey K.M., Heirich K., Renier C., Vilches-Moure J.G., Gupta R., Razmara A.M., Zhang H., et al. Investigating circulating tumor cells and distant metastases in patient-derived orthotopic xenograft models of triple-negative breast cancer. Breast Cancer Res. 2019;21:98. doi: 10.1186/s13058-019-1182-4. PubMed DOI PMC

Sikandar S.S., Kuo A.H., Kalisky T., Cai S., Zabala M., Hsieh R.W., Lobo N.A., Scheeren F.A., Sim S., Qian D., et al. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nat. Commun. 2017;8:1669. doi: 10.1038/s41467-017-01666-2. PubMed DOI PMC

Hugo H.J., Gunasinghe N., Hollier B.G., Tanaka T., Blick T., Toh A., Hill P., Gilles C., Waltham M., Thompson E.W. Epithelial requirement for in vitro proliferation and xenograft growth and metastasis of MDA-MB-468 human breast cancer cells: Oncogenic rather than tumor-suppressive role of E-cadherin. Breast Cancer Res. 2017;19:86. doi: 10.1186/s13058-017-0880-z. PubMed DOI PMC

Padmanaban V., Krol I., Suhail Y., Szczerba B.M., Aceto N., Bader J.S., Ewald A.J. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573:439–444. doi: 10.1038/s41586-019-1526-3. PubMed DOI PMC

Bonnomet A., Syne L., Brysse A., Feyereisen E., Thompson E.W., Noel A., Foidart J.M., Birembaut P., Polette M., Gilles C. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene. 2012;31:3741–3753. doi: 10.1038/onc.2011.540. PubMed DOI

Stankic M., Pavlovic S., Chin Y., Brogi E., Padua D., Norton L., Massague J., Benezra R. TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 2013;5:1228–1242. doi: 10.1016/j.celrep.2013.11.014. PubMed DOI PMC

Gao D., Joshi N., Choi H., Ryu S., Hahn M., Catena R., Sadik H., Argani P., Wagner P., Vahdat L.T., et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 2012;72:1384–1394. doi: 10.1158/0008-5472.CAN-11-2905. PubMed DOI PMC

Carey L.A., Dees E.C., Sawyer L., Gatti L., Moore D.T., Collichio F., Ollila D.W., Sartor C.I., Graham M.L., Perou C.M. The triple negative paradox: Primary tumor chemosensitivity of breast cancer subtypes. Clin. Cancer Res. 2007;13:2329–2334. doi: 10.1158/1078-0432.CCR-06-1109. PubMed DOI

Liedtke C., Mazouni C., Hess K.R., Andre F., Tordai A., Mejia J.A., Symmans W.F., Gonzalez-Angulo A.M., Hennessy B., Green M., et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 2008;26:1275–1281. doi: 10.1200/JCO.2007.14.4147. PubMed DOI

Bhola N.E., Balko J.M., Dugger T.C., Kuba M.G., Sanchez V., Sanders M., Stanford J., Cook R.S., Arteaga C.L. TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J. Clin. Investig. 2013;123:1348–1358. doi: 10.1172/JCI65416. PubMed DOI PMC

Park S.Y., Kim M.J., Park S.A., Kim J.S., Min K.N., Kim D.K., Lim W., Nam J.S., Sheen Y.Y. Combinatorial TGF-beta attenuation with paclitaxel inhibits the epithelial-to-mesenchymal transition and breast cancer stem-like cells. Oncotarget. 2015;6:37526–37543. doi: 10.18632/oncotarget.6063. PubMed DOI PMC

Bandyopadhyay A., Wang L., Agyin J., Tang Y., Lin S., Yeh I.T., De K., Sun L.Z. Doxorubicin in combination with a small TGFbeta inhibitor: A potential novel therapy for metastatic breast cancer in mouse models. PLoS ONE. 2010;5:e10365. doi: 10.1371/journal.pone.0010365. PubMed DOI PMC

Raza U., Saatci O., Uhlmann S., Ansari S.A., Eyupoglu E., Yurdusev E., Mutlu M., Ersan P.G., Altundag M.K., Zhang J.D., et al. The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer. Oncotarget. 2016;7:49859–49877. doi: 10.18632/oncotarget.10489. PubMed DOI PMC

Yoshida T., Ozawa Y., Kimura T., Sato Y., Kuznetsov G., Xu S., Uesugi M., Agoulnik S., Taylor N., Funahashi Y., et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. Br. J. Cancer. 2014;110:1497–1505. doi: 10.1038/bjc.2014.80. PubMed DOI PMC

Dominguez C., McCampbell K.K., David J.M., Palena C. Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI Insight. 2017;2 doi: 10.1172/jci.insight.94296. PubMed DOI PMC

Alsuliman A., Colak D., Al-Harazi O., Fitwi H., Tulbah A., Al-Tweigeri T., Al-Alwan M., Ghebeh H. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells. Mol. Cancer. 2015;14:149. doi: 10.1186/s12943-015-0421-2. PubMed DOI PMC

Williams E.D., Gao D.C., Redfern N., Thompson E.W. Controversies around epithelial-mesenchymal plasticity in cancer metastasis. Nat. Rev. Cancer. 2019;19:716–732. doi: 10.1038/s41568-019-0213-x. PubMed DOI PMC

Hari K., Sabuwala B., Subramani B.V., La Porta C.A.M., Zapperi S., Font-Clos F., Jolly M.K. Identifying inhibitors of epithelial-mesenchymal plasticity using a network topology-based approach. NPJ Syst. Biol. Appl. 2020;6:15. doi: 10.1038/s41540-020-0132-1. PubMed DOI PMC

Celia-Terrassa T., Bastian C., Liu D.D., Ell B., Aiello N.M., Wei Y., Zamalloa J., Blanco A.M., Hang X., Kunisky D., et al. Author Correction: Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat. Commun. 2019;10:527. doi: 10.1038/s41467-019-08509-2. PubMed DOI PMC

Single-cell protein profiling defines cell populations associated with triple-negative breast cancer aggressiveness