Abstract
Epithelial mesenchymal transition (EMT) has long been associated with breast cancer cell invasiveness and evidence of EMT processes in clinical samples is growing rapidly. Genome-wide transcriptional profiling of increasingly larger numbers of human breast cancer (HBC) cell lines have confirmed the existence of a subgroup of cell lines (termed Basal B/Mesenchymal) with enhanced invasive properties and a predominantly mesenchymal gene expression signature, distinct from subgroups with predominantly luminal (termed Luminal) or mixed basal/luminal (termed Basal A) features (Neve et al Cancer Cell 2006). Studies providing molecular and cellular analyses of EMT features in these cell lines are summarised, and the expression levels of EMT-associated factors in these cell lines are analysed. Recent clinical studies supporting the presence of EMT-like changes in vivo are summarised. Human breast cancer cell lines with mesenchymal properties continue to hold out the promise of directing us towards key mechanisms at play in the metastatic dissemination of breast cancer.
Similar content being viewed by others
Abbreviations
- EMT:
-
Epithelial mesenchymal transition
- EGF:
-
Epidermal growth factor
- HBC:
-
Human breast cancer
- IGF-IR:
-
Type I insulin-like growth factor receptor
- MET:
-
Mesenchymal epithelial transition
- TNFα:
-
Tumor necrosis factor alpha
References
Duband JL, Monier F, Delannet M, Newgreen D (1995) Epithelium-mesenchyme transition during neural crest development. Acta Anat (Basel) 154(1):63–78
Prindull G, Zipori D (2004) Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 103(8):2892–2899
Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142
Zavadil J, Bottinger EP (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24(37):5764–5774
Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17(5):548–558
Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198(1):11–26
Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15(6):740–746
Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562
Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132(14):3151–3161
Przybylo JA, Radisky DC (2007) Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail’s pace. Int J Biochem Cell Biol 39(6):1082–1088
Thomson S, Buck E, Petti F et al (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65(20):9455–9462
Tarin D, Thompson EW, Newgreen DF (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65(14):5996–6000 discussion -1
Thompson EW, Newgreen DF, Tarin D (2005) Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 65(14):5991–5995 discussion 5
Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66(17):8319–8326
Aigner K, Dampier B, Descovich L et al (2007) The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26(49):6979–6988
Hlubek F, Spaderna S, Schmalhofer O, Jung A, Kirchner T, Brabletz T (2007) Wnt/FZD signaling and colorectal cancer morphogenesis. Front Biosci 12:458–470
Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981
Liu Y (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15(1):1–12
Zeisberg M, Kalluri R (2004) The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med 82(3):175–181
Zeisberg M, Yang C, Martino M, Duncan M, Rieder F, Tanjore H, Kalluri R (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282(32):23337–23347
Mercado-Pimentel ME, Runyan RB (2007) Multiple transforming growth factor-beta isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart. Cells Tissues Organs 185(1–3):146–156
Arciniegas E, Frid MG, Douglas IS, Stenmark KR (2007) Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 293(1):L1–L8
Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428
Thompson EW, Paik S, Brunner N et al (1992) Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 150(3):534–544
Sommers CL, Heckford SE, Skerker JM, Worland P, Torri JA, Thompson EW, Byers SW, Gelmann EP (1992) Loss of epithelial markers and acquisition of vimentin expression in adriamycin- and vinblastine-resistant human breast cancer cell lines. Cancer Res 52(19):5190–5197
Gilles C, Polette M, Zahm J, Tournier J, Volders L, Foidart J, Birembaut P (1999) Vimentin contributes to human mammary epithelial cell migration. J Cell Sci 112(Pt 24):4615–4625
Sommers CL, Byers SW, Thompson EW, Torri JA, Gelmann EP (1994) Differentiation state and invasiveness of human breast cancer cell lines. Breast Cancer Res Treat 31(2–3):325–335
Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 147(3):631–644
Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA (2000) Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 148(4):779–790
Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M (2007) Vimentin and epithelial-mesenchymal transition in human breast cancer-observations in vitro and in vivo. Cells Tissues Organs 185(1–3):191–203
Hendrix MJ, Seftor EA, Seftor RE, Trevor KT (1997) Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. Am J Pathol 150(2):483–495
Jungert K, Buck A, von Wichert G, Adler G, Konig A, Buchholz M, Gress TM, Ellenrieder V (2007) Sp1 is required for transforming growth factor-beta-induced mesenchymal transition and migration in pancreatic cancer cells. Cancer Res 67(4):1563–1570
Vasko V, Espinosa AV, Scouten W et al (2007) Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA 104(8):2803–2808
Gilles C, Newgreen D, Sato H, Thompson EW (2004) Matrix Metalloproteases and epithelial-to mesenchymal transition: implications for carcinoma metastasis In: P Savagner (ed) Rise and fall of epithelial phenotype (webversion at www.eurekah.com). Landes Bioscience Publishers, Georgetown, TX, pp 297–315
Giunciuglio D, Culty M, Fassina G et al (1995) Invasive phenotype of MCF10A cells overexpressing c-Ha-ras and c-erbB-2 oncogenes. Int J Cancer 63(6):815–822
Kim HJ, Litzenburger BC, Cui X et al (2007) Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol 27(8):3165–3175
Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H (2007) NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 26(5):711–724
Li GC, Wang ZY (2006) Constitutive expression of RbAp46 induces epithelial-mesenchymal transition in mammary epithelial cells. Anticancer Res 26(5A):3555–3560
Perou CM, Jeffrey SS, van de Rijn M et al (1999) Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci USA 96(16):9212–9217
Thompson EW, Torri J, Sabol M et al (1994) Oncogene-induced basement membrane invasiveness in human mammary epithelial cells. Clin Exp Metastasis 12(3):181–194
Galliher AJ, Schiemann WP (2006) Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res 8(4):R42
Planas -Silva MD, Waltz PK (2007) Estrogen promotes reversible epithelial-to-mesenchymal-like transition and collective motility in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 104(1–2):11–21
Shtutman M, Levina E, Ohouo P, Baig M, Roninson IB (2006) Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res 66(23):11370–11380
Whitehead RH, Bertoncello I, Webber LM, Pedersen JS (1983) A new human breast carcinoma cell line (PMC42) with stem cell characteristics. I. Morphologic characterization. J Natl Cancer Inst 70(4):649–661
Whitehead RH, Monaghan P, Webber LM, Bertoncello I, Vitali AA (1983) A new human breast carcinoma cell line (PMC42) with stem cell characteristics. II. Characterization of cells growing as organoids. J Natl Cancer Inst 71(6):1193–1203
Whitehead RH, Quirk SJ, Vitali AA, Funder JW, Sutherland RL, Murphy LC (1984) A new human breast carcinoma cell line (PMC42) with stem cell characteristics. III. Hormone receptor status and responsiveness. J Natl Cancer Inst 73(3):643–648
Hugo, Ackland ML, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial––mesenchymal and mesenchymal––epithelial transitions in carcinoma progression. J Cell Physiol 213(2):374–383
Ackland ML, Michalczyk A, Whitehead RH (2001) PMC42, A novel model for the differentiated human breast. Exp Cell Res 263(1):14–22
Lebret SC, Newgreen DF, Waltham MC, Price JT, Thompson EW, Ackland ML (2006) Myoepithelial molecular markers in human breast carcinoma PMC42-LA cells are induced by extracellular matrix and stromal cells. In vitro Cell Dev Biol Anim 42(10):298–307
Ackland ML, Newgreen D, Price JT, Fridman M, Waltham M, Arvanitis A, Minichiello J, Thompson EW (2003) Epidermal growth factor stimulates epithelio-mesenchymal transition in the stable human breast carcinoma cell line variant PMC42-LA. Lab Invest 83(3):435–448
Lebret SC, Newgreen DF, Thompson EW, Ackland ML (2007) Induction of epithelial to mesenchymal transition in PMC42-LA human breast carcinoma cells by carcinoma-associated fibroblast secreted factors. Breast Cancer Res 9(1):R19
Thiery JP (2002) Epithelial to mesenchymal transitions in tumour progression. Nature Cancer 2:442–454
Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66(23):11271–11278
Chaffer CL, Dopheide B, McCulloch DR, Lee AB, Moseley JM, Thompson EW, Williams ED (2005) Upregulated MT1-MMP/TIMP-2 axis in the TSU-Pr1-B1/B2 model of metastatic progression in transitional cell carcinoma of the bladder. Clin Exp Metastasis 22(2):115–125
Come C, Magnino F, Bibeau F, De Santa Barbara P, Becker KF, Theillet C, Savagner P (2006) Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 12(18):5395–5402
Ross DT, Scherf U, Eisen MB et al (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24(3):227–235
Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD (2007) MDA-MB-435 cells are derived from M14 Melanoma cells–a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res Treat 104(1):13–19
Zajchowski DA, Bartholdi MF, Gong Y et al (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61(13):5168–5178
Lacroix M, Leclercq G (2004) Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83(3):249–289
Lombaerts M, van Wezel T, Philippo K et al (2006) E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer 94(5):661–671
Charafe-Jauffret E, Ginestier C, Monville F et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25(15):2273–2284
Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–577
El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J (2000) Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. Hum Mol Genet 9(5):813–819
Chen B, Lim RW (1997) Physical and functional interactions between the transcriptional inhibitors Id3 and ITF-2b. Evidence toward a novel mechanism regulating muscle-specific gene expression. J Biol Chem 272(4):2459–2463
Maira SM, Wurtz JM, Wasylyk B (1996) Net (ERP/SAP2) one of the Ras-inducible TCFs, has a novel inhibitory domain with resemblance to the helix-loop-helix motif. Embo J 15(21):5849–5865
Brabletz T, Jung A, Hermann K, Gunther K, Hohenberger W, Kirchner T (1998) Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 194(10):701–704
Gilles C, Thompson EW (1996) The epithelial to mesenchymal transition and metastatic progression in carcinoma. The Brea J 2:83–96
Korsching E, Packeisen J, Liedtke C et al (2005) The origin of vimentin expression in invasive breast cancer: epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 206(4):451–457
Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA (2002) Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21(20):3241–3246
Cheng CW, Wu PE, Yu JC, Huang CS, Yue CT, Wu CW, Shen CY (2001) Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene 20(29):3814–3823
Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I, Reich R, Davidson B (2005) Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103(8):1631–1643
Moody SE, Perez D, Pan TC et al (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8(3):197–209
Martin TA, Goyal A, Watkins G, Jiang WG (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496
Come C, Arnoux V, Bibeau F, Savagner P (2004) Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. J Mammary Gland Biol Neoplasia 9(2):183–193
Mironchik Y, Winnard PT Jr., Vesuna F et al (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65(23):10801–10809
Aigner K, Descovich L, Mikula M et al (2007) The transcription factor ZEB1 (deltaEF1) represses Plakophilin 3 during human cancer progression. FEBS Lett 581(8):1617–1624
Turashvili G, Bouchal J, Baumforth K et al (2007) Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer 7:55
Dupont VN, Gentien D, Oberkampf M, De Rycke Y, Blin N (2007) A gene expression signature associated with metastatic cells in effusions of breast carcinoma patients. Int J Cancer 121(5):1036–1046
Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, Argani P, Sukumar S (2006) HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res 66(19):9527–9534
Castro Alves C, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, Carneiro F, Becker KF (2007) Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol 211(5):507–515
Alonso SR, Tracey L, Ortiz P et al (2007) A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Cancer Res 67(7):3450–3460
Chung CH, Parker JS, Ely K et al (2006) Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-{kappa}B signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 66(16):8210–8218
Yuen HF, Chua CW, Chan YP, Wong YC, Wang X, Chan KW (2007) Significance of TWIST and E-cadherin expression in the metastatic progression of prostatic cancer. Histopathology 50(5):648–658
Uchikado Y, Natsugoe S, Okumura H, Setoyama T, Matsumoto M, Ishigami S, Aikou T (2005) Slug Expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res 11(3):1174–1180
Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446(7136):690–694
Horikawa T, Yang J, Kondo S, Yoshizaki T, Joab I, Furukawa M, Pagano JS (2007) Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma. Cancer Res 67(5):1970–1978
Lee TK, Poon RT, Yuen AP et al (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12(18):5369–5376
Finn RS, Dering J, Ginther C, Wilson CA, Glaspy P, Tchekmedyian N, Slamon DJ (2007) Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/”triple-negative” breast cancer cell lines growing in vitro. Breast Cancer Res Treat 105(3):319–326
Buck E, Eyzaguirre A, Barr S et al (2007) Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther 6(2):532–541
Yang AD, Fan F, Camp ER et al (2006) Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 12(14 Pt 1):4147–4153
Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752
Ross DT, Perou CM (2001) A comparison of gene expression signatures from breast tumors and breast tissue derived cell lines. Dis Markers 17(2):99–109
Kenny PA, Lee GY, Myers CA et al (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 1:84–96
Hugo, Ackland ML, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression. J Cell Physiol 213(2):374–383
Thompson EW, Waltham M, Ramus SJ, Hutchins AM, Armes JE, Campbell IG, Williams ED, Thompson PR, Rae JM, Johnson MD, Clarke R (2004) LCC15-MB cells are MDA-MB-435: a review of misidentified breast and prostate cell lines. Clin Exp Metastasis 21(6):535–541
Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7(6):1267–1278
Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noel A, van Roy F, Berx G, Foidart JM, Gilles C (2006) Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene 25(36):4975–4985
Espineda CE, Chang JH, Twiss J, Rajasekaran SA, Rajasekaran AK (2004) Repression of Na, K-ATPase beta1-subunit by the transcription factor snail in carcinoma. Mol Biol Cell 15(3):1364-1373
Okubo T, Truong TK, Yu B, Itoh T, Zhao J, Grube B, Zhou D, Chen S (2001) Down-regulation of promoter 1.3 activity of the human aromatase gene in breast tissue by zinc-finger protein, snail (SnaH). Cancer Res 61(4):1338–1346
Rennstam K, Jonsson G, Tanner M, Bendahl PO, Staaf J, Kapanen AI, Karhu R, Baldetorp B, Borg A, Isola J (2007) Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1. Cancer Genet Cytogenet 172(2):95–106
Acknowledgements
This research was funded in part by the U.S. Army Medical Research and Materiel Command (DAMD17-03-1-0416) to EWT. TB and EWT are supported in part by the Victorian Breast Cancer Research Consortium. EW is the recipient of an AUS Aid Scholarship. Parts of this work were also supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research (Contract DE-AC03-76SF00098) and the California Breast Cancer Research Program (CBCRP) grant # 7FB-0027.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blick, T., Widodo, E., Hugo, H. et al. Epithelial mesenchymal transition traits in human breast cancer cell lines . Clin Exp Metastasis 25, 629–642 (2008). https://doi.org/10.1007/s10585-008-9170-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10585-008-9170-6