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Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women

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Cancer Microenvironment

Abstract

Breast cancer (BC) in Oman affects younger women and has a more aggressive course. Clinical and biological variables like age, pregnancy, tumor size, type, grade, receptor expression and proliferation predict disease aggression but there is no direct predictor of metastasis except lymphovascular invasion. Epithelial-mesenchymal transition (EMT) is characterized by epithelial cells losing epithelial and acquiring mesenchymal morpho-immunophenotypic characteristics. In tumors, EMT-like transitions may signify a metastatic phenotype and have features in common with cancer stem cells (CSC) which show resistance to chemotherapy. This study aimed to identify EMT and CSC phenotypes in metastatic and non-metastatic breast cancer in Omani women and their association with conventional clinico-pathological predictors of BC. In a retrospective study of ninety-six Omani women with breast cancer, the association of age, pregnancy/lactation, tumor size, type, grade, ductal carcinoma insitu (DCIS), lymphovascular invasion, hormone/ HER2 receptor expression and Ki67 proliferation index (Ki67 PI) was tested with EMT/ CSC phenotype and metastasis. Young age ≤ 40 years, lymphovascular invasion and EMT had a strong association with metastasis; CSC approached significance. Vimentin expression in tumor cells, fibronectin and MMP-11 in stroma were reliable markers of EMT; dual EMT and CSC phenotype (Vim+/ CD44+/ CD 24−/low) had a strong association with apocrine variant, basal-like tumors and triple negative cancers. EMT had a strong association with Ki67 proliferation index (PI) and CSC with HER2-like tumors and distant metastasis. These select markers may be useful in metastasis-prediction in pre-treatment biopsies.

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References

  1. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Witz IP. The tumor microenvironment: the making of a paradigm. Tumor Microenvironment 2(1):S9-S17

  3. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  CAS  PubMed  Google Scholar 

  4. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 7(21):10123–10128

    Article  Google Scholar 

  5. Orimo A, Gupta PB, Sgroi DC, Seisdedos A, Delauney T, Naem R et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 21(3):335–348

    Article  Google Scholar 

  6. Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 4(6):818–829

    Article  Google Scholar 

  7. Gupta GP, Massague J (2006) Cancer Metastasis: building a framework. Cell 127(4):679–695

    Article  CAS  PubMed  Google Scholar 

  8. Park CC, Bissell MJ, Barcellos-Hoff MH (2000) The influence of the microenvironment on the malignant phenotype. Mol Med Today 6:324–329

    Article  CAS  PubMed  Google Scholar 

  9. Sager R (1997) Expression genetics in cancer: shifting the focus from DNA to RNA. Proc Natl Acad Sci U S A 94:952–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749

    Article  CAS  PubMed  Google Scholar 

  11. Gangopadhyay S, Nandy A, Hor P, Mukhopadhyay A (2013) Breast cancer stem cells: a novel therapeutic target. Clin Breast Cancer 3(1):7–15

    Article  Google Scholar 

  12. Mani SA, Guo W, Liao MJ, Eaton EN, Ayannan A, Zhou AY et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL et al (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69(14):5820–5828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67(5):1979–1987

    Article  CAS  PubMed  Google Scholar 

  15. Thomson S, Petti F, Sujka-Kwok I, Mercado P, Bean J, Monaghan M, Seymour SL, Argast GM, Epstein DM, Haley JD (2011) A systems view of epithelial–mesenchymal transition signaling states. Clin Exp Metastasis 28:137–155

    Article  CAS  PubMed  Google Scholar 

  16. Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109:2784–2789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tiwari N, Gheldof A, Tatari M, Christofori G (2012) EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 22:194–207

    Article  CAS  PubMed  Google Scholar 

  18. Tomaskovik-Crook E, Thompsom EW, Thiery JP (2009) Epithelial to mesenchymal transition and breast cancer. Breast Cancer Res 11(6):213

    Article  Google Scholar 

  19. Kimbung S, Kovaks A, Bendahl P-A, Malmstrom P, Ferno M, Hatschek T, Hedenfalk I (2013) Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences. Mol Oncol. doi:10.1016/j.molonc.2013.10.002

  20. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A (2009) Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 106(33):13820–13825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, Kim YJ, Kim JH, Park SY (2013) Tumor infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer 109:2705–2713. doi:10.1038/bjc.2013.634

  22. Kumar S, Burney A, al-Ajmi A, al-Moundhri M (2011) Changing trends of breast cancer survival in Sultanate of Oman. J Oncol. doi:10.1155/2011/316243

  23. Bharat A, Aft RL, Gao F, Margenthaler JA (2009) Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer. J Surg Oncol 100(3):248–251. doi:10.1002/jso.21268

    Article  PubMed  Google Scholar 

  24. Colleoni M, Anders CK (2013) Debate: the biology of breast cancer in young women is unique. Oncologist 18(4):e13–e15. doi:10.1634/theoncologist.2013-0118

    Article  PubMed  Google Scholar 

  25. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) AJCC cancer staging manual. Springer-Verlag, New York

    Google Scholar 

  26. Lakhani S (2012) WHO classification of tumours of the breast. International Agency for Research on Cancer, Lyon

    Google Scholar 

  27. Elston CW, Ellis I O (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 19; 403-410. Author Commentary Histopathology 2002; 41(3A):151–2

  28. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168

    CAS  PubMed  Google Scholar 

  29. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ et al (2007) American society of clinical oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145

    Article  CAS  PubMed  Google Scholar 

  30. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ (2011) Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Ann Oncol 22:1736–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Glentis A, Gurchenkov V, Matic Vignjevic D (2014) Assembly, heterogeneity, and breaching of the basement membranes. Cell Adhes Migr 8(3):236–245

    Article  Google Scholar 

  32. Pogány G, Timár F, Oláh J, Harisi R, Polony G, Paku S et al (2001) Role of the basement membrane in tumor cell dormancy and cytotoxic resistance. Oncology 60(3):274–281

    Article  PubMed  Google Scholar 

  33. Harisi R, Kenessey I, Olah JN, Timar F, Babo I, Pogany G et al (2009) Differential inhibition of single and cluster type tumor cell migration. Anticancer Res 29(8):2981–2985

    PubMed  Google Scholar 

  34. Nadir Y, Brenner B (2014) Heparanase multiple effects in cancer. Thromb Res 133(Suppl 2):S90–S94. doi:10.1016/S0049-3848(14)50015-1

    Article  CAS  PubMed  Google Scholar 

  35. Böger C, Warneke VS, Behrens HM, Kalthoff H, Goodman SL, Becker T, Röcken C (2014) Integrins αvβ 3 and α vβ 5 as prognostic, diagnostic, and therapeutic targets in gastric cancer. Gastric Cancer 18(4):784–795. doi:10.1007/s10120-014-0435-2

    Article  PubMed  PubMed Central  Google Scholar 

  36. Harisi R, Jeney A (2015) Extracellular matrix as target for antitumor therapy. Onco Targets Ther 8:1387–1398. doi:10.2147/OTT.S48883

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jia Y, Chen Y, Wang Q, Jaysinghe U, Luo X, Wei Q et al. (2017) Exosome: emerging biomarker in breast cancer. Oncotarget. 2017 mar 29. doi: 10.18632/oncotarget.16684

  38. Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119(6):1429–1437. doi:10.1172/JCI36183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548–558

    Article  CAS  PubMed  Google Scholar 

  40. Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H (2005) Transcriptional activation of integrin beta6 during the epithelial mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 115:339–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Raymond WA, Leong AS (1989) Vimentin--a new prognostic parameter in breast carcinoma? J Pathol 158:107–114

    Article  CAS  PubMed  Google Scholar 

  42. Roussos ET, Keckesova Z, Haley JD, Epstein DM, Weinberg RA, Condeelis JS (2010) AACR special conference on epithelial-mesenchymal transition and cancer progression and treatment. Cancer Res 70(19):7360–7364. doi:10.1158/0008-5472.CAN-10-1208

    Article  CAS  PubMed  Google Scholar 

  43. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68:989–997

    Article  CAS  PubMed  Google Scholar 

  44. Lima JF, Nofech-Mozes S, Bayani J, John M, Bartlett S (2016) EMT in Breast Carcinoma—A Review. J Clin Med 5(7):65. Published online 2016 Jul 14. doi:10.3390/jcm5070065

    Article  Google Scholar 

  45. Brabletz T, Jung A, Hermann K, Günther 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 194:701–704

    Article  CAS  PubMed  Google Scholar 

  46. Christensen L (1992) The distribution of fibronectin, laminin and tetranectin in human breast cancer with special attention to the extracellular matrix. APMIS Suppl 26:1–39

    CAS  PubMed  Google Scholar 

  47. Carpenter PM, Wang-Rodriguez J, Chan OT, Wilczynski SP (2008) Laminin 5 expression in metaplastic breast carcinomas. Am J Surg Pathol 32:345–353

    Article  PubMed  Google Scholar 

  48. Barrallo-Gimeno A, Nieto MA (2005) The snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132:3151–3161

    Article  CAS  PubMed  Google Scholar 

  49. Yang Z, Zhang X, Gang H, Li X, Li Z, Wang T et al (2007) Up-regulation of gastric cancer cell invasion by twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun 358:925–930

    Article  CAS  PubMed  Google Scholar 

  50. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601

    Article  CAS  PubMed  Google Scholar 

  51. Foroni C, Broggini M, Generali D, Damia G (2012) Epithelial-mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. Cancer Treat Rev 38(6):689–697. doi:10.1016/j.ctrv.2011.11.001

    Article  CAS  PubMed  Google Scholar 

  52. Abraham BK, Fritz P, McClellan M, Hauptvogel P, Athelogou M, Brauch H (2005) Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11:1154–1159

    CAS  PubMed  Google Scholar 

  53. Al-Ejeh F, Smart CE, Morrison BJ, Chenevix-Trench G, Lopez JA, Lakhani SR et al (2011) Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis 32:650–658

    Article  CAS  PubMed  Google Scholar 

  54. Sharma P (2016) Biology and Management of Patients with Triple-Negative Breast Cancer. Oncologist 21(9):1050–1062. doi:10.1634/theoncologist.2016-0067

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y et al (2016) Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS one 11(6):e0157368. doi:10.1371/journal.pone.0157368

    Article  PubMed  PubMed Central  Google Scholar 

  56. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76

    Article  PubMed  PubMed Central  Google Scholar 

  57. 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 185:191–203

    Article  CAS  PubMed  Google Scholar 

  58. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100:672–679

    Article  CAS  PubMed  Google Scholar 

  60. Marcucci F, Ghezzi P, Rumio C (2017) The role of autophagy in the cross-talk between epithelial-mesenchymal transitioned tumor cells and cancer stem-like cells. Mol Cancer 16(1):3. doi:10.1186/s12943-016-0573-8

    Article  PubMed  PubMed Central  Google Scholar 

  61. Johansson AL, Andersson TM, Hsieh CC, Cnattingius S, Lambe M (2011) Increased mortality in women with breast cancer detected during pregnancy and different periods postpartum. Cancer Epidemiol Biomark Prev 20(9):1865–1872

    Article  Google Scholar 

  62. Sung CO, Park CK, Kim SH (2011) Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis. Mod Pathol 24:1060–1068

    Article  PubMed  Google Scholar 

  63. Ryu HS, Park DJ, Kim HH, Kim WH, Lee HS (2012) Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer. Hum Pathol 43:520–528

    Article  PubMed  Google Scholar 

  64. Bae YK, Choi JE, Kang SH, Lee SJ (2015) Epithelial-mesenchymal transition phenotype is associated with Clinicopathological factors that indicate aggressive biological behavior and poor clinical outcomes in invasive breast cancer. J Breast Cancer 18(3):256–263. doi:10.4048/jbc.2015.18.3.256

    Article  PubMed  PubMed Central  Google Scholar 

  65. Pomp V, Leo C, Mauracher A, Korol D, Guo W, Varga Z (2015) Differential expression of epithelial–mesenchymal transition and stem cell markers in intrinsic subtypes of breast cancer. Breast Cancer Res Treat 154(1):45–55

    Article  CAS  PubMed  Google Scholar 

  66. Domagala W, Lasota J, Bartkowiak J, Weber K, Osborn M (1990) Vimentin is preferentially expressed in human breast carcinomas with low estrogen receptor and high Ki-67 growth fraction. J Pathol 136(1):219–227

    CAS  Google Scholar 

  67. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D et al (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R (2008) Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther 7:464–473

    Article  CAS  PubMed  Google Scholar 

  69. Shiyang W, Suyan L, Zhiming L, Jiefeng H, Xiaoyu P, Jing L et al (2015) Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One 10(4):e0123976. doi:10.1371/journal.pone.0123976

    Article  Google Scholar 

  70. Tachtsidis A, McInnes LM, Jacobsen N, Thompson EW, Saunders CM (2016) Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells. Clin Exp Metastasis 33(6):521–550. doi:10.1007/s10585-016-9796-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Desai K, Aiyappa R, Prabhu JS, Nair MG, Lawrence PV, Korlimarla A et al (2017) HR+HER2- breast cancers with growth factor receptor-mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells. Tumour Biol 39(3):1010428317695028. doi:10.1177/1010428317695028

    Article  PubMed  Google Scholar 

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Acknowledgements

This paper is derived from research carried out at Sultan Qaboos University funded by Internal grant IG/MED/PATH/15. Technical laboratory assistance by Chief BMS Johanes Selva Kumar and secretarial support by Edna B Ranada is gratefully acknowledged.

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Authors and Affiliations

  1. Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates

    Ritu Lakhtakia

  2. Sultan Qaboos University Hospital, Muscat, Oman

    Adil Aljarrah

  3. Shifa Medical Center, Shifa International Hospital, Islamabad, Pakistan

    Muhammad Furrukh

  4. College of Medicine, Sultan Qaboos University, Muscat, Oman

    Shyam S. Ganguly

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  1. Ritu Lakhtakia
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  2. Adil Aljarrah
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Lakhtakia, R., Aljarrah, A., Furrukh, M. et al. Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women. Cancer Microenvironment 10, 25–37 (2017). https://doi.org/10.1007/s12307-017-0194-9

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