Advertisement

Cancer Causes & Control

, Volume 30, Issue 1, pp 41–51 | Cite as

Potential protein markers for breast cancer recurrence: a retrospective cohort study

  • Chunyan HeEmail author
  • Rina Plattner
  • Vivek Rangnekar
  • Binhua Zhou
  • Chunming Liu
  • Rachel L. Stewart
  • Bin Huang
  • Chi Wang
  • Thomas C. TuckerEmail author
Original paper
First Online:
  • 58 Downloads

Abstract

Background

We evaluated five key proteins involved in various cancer-related pathways and assessed their relation to breast cancer recurrence.

Methods

We used the Kentucky Cancer Registry to retrospectively identify primary invasive breast cancer cases (n = 475) that were diagnosed and treated at University of Kentucky Medical Center between 2000 and 2007. Breast cancer recurrence was observed in 62 cases during the 5-year follow-up after diagnosis. Protein expression or activity level was analyzed from surgery tissue using immuno-histochemical assays.

Results

Compared to ER+/PR+/HER2− patients without recurrence, those with recurrence had higher TWIST expression (p = 0.049) but lower ABL1/ABL2 activity (p = 0.003) in primary tumors. We also found that triple-negative breast cancer patients with recurrence had higher SNAI1 expression compared to those without recurrence (p = 0.03). After adjusting for potential confounders, the higher ABL1/ABL2 activity in primary tumors was associated with a decreased risk of recurrence (OR 0.72, 95% CI 0.85–0.90) among ER+/PR+/HER2− patients. In addition, among patients with recurrence we observed that the activity level of ABL1/ABL2 was significantly increased in recurrent tumors compared to the matched primary tumors regardless of the subtype (p = 0.013).

Conclusions

These findings provide evidence that the expression/activity level of various proteins may be differentially associated with risk of recurrence of breast tumor subtypes.

Keywords

Breast cancer Recurrence Biomarkers Protein expression Protein activity Tumor subtypes 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

Special thanks to Dana Napier for her expertise in TMA construction and talent with immunohistochemistry. Drs. He, Plattner, Rangnekar, Zhou, and Tucker are supported by the University of Kentucky Markey Cancer Center (P30CA177558). Dr. Stewart is supported by NIH fellowship Grant T32 CA160003. The Markey Cancer Center’s Research Communications Office assisted with preparation of this manuscript.

Funding

This research project was supported by Markey Cancer Center pilot funding IRB# 14-0172-P3H, the Biospecimen Procurement and Translational Pathology, the Biostatistics and Bioinformatics, and the Cancer Research Informatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558).

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10552_2018_1099_MOESM1_ESM.pdf (126 kb)
Supplementary material 1 (PDF 125 KB)
10552_2018_1099_MOESM2_ESM.pdf (72 kb)
Supplementary material 2 (PDF 71 KB)
10552_2018_1099_MOESM3_ESM.pdf (1.6 mb)
Supplementary material 3 (PDF 1640 KB)
10552_2018_1099_MOESM4_ESM.docx (649 kb)
Supplementary material 4 (DOCX 649 KB)
10552_2018_1099_MOESM5_ESM.docx (16 kb)
Supplementary material 5 (DOCX 16 KB)

References

  1. 1.
    Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30PubMedGoogle Scholar
  2. 2.
    Guarneri V, Dieci MV, Conte P (2013) Relapsed triple-negative breast cancer: challenges and treatment strategies. Drugs 73(12):1257–1265PubMedGoogle Scholar
  3. 3.
    Hockel M, Dornhofer N (2005) The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection. Cancer Res 65(8):2997–3002PubMedGoogle Scholar
  4. 4.
    Redig AJ, McAllister SS (2013) Breast cancer as a systemic disease: a view of metastasis. J Intern Med 274(2):113–126PubMedPubMedCentralGoogle Scholar
  5. 5.
    Tevaarwerk AJ, Gray RJ, Schneider BP, Smith ML, Wagner LI, Fetting JH, Davidson N, Goldstein LJ, Miller KD, Sparano JA (2013) Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: little evidence of improvement over the past 30 years. Cancer 119(6):1140–1148PubMedGoogle Scholar
  6. 6.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037PubMedGoogle Scholar
  7. 7.
    Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826PubMedGoogle Scholar
  8. 8.
    van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009PubMedGoogle Scholar
  9. 9.
    Buyse M, Loi S, van’t Veer L, Viale G, Delorenzi M, Glas AM, d’Assignies MS, Bergh J, Lidereau R, Ellis P et al (2006) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98(17):1183–1192PubMedGoogle Scholar
  10. 10.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27(8):1160–1167PubMedPubMedCentralGoogle Scholar
  11. 11.
    de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C (2009) Global signatures of protein and mRNA expression levels. Mol Biosyst 5(12):1512–1526PubMedGoogle Scholar
  12. 12.
    Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13(4):227–232PubMedPubMedCentralGoogle Scholar
  13. 13.
    Maier T, Guell M, Serrano L (2009) Correlation of mRNA and protein in complex biological samples. FEBS Lett 583(24):3966–3973Google Scholar
  14. 14.
    Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou A, Pant D, Grimley JS, Wandless TJ, Demichele A, Investigators IST et al (2013) Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 24(1):30–44PubMedGoogle Scholar
  15. 15.
    Hebbar N, Wang C, Rangnekar VM (2012) Mechanisms of apoptosis by the tumor suppressor Par-4. J Cell Physiol 227(12):3715–3721PubMedPubMedCentralGoogle Scholar
  16. 16.
    Mendez-Lopez LF, Zapata-Benavides P, Zavala-Pompa A, Aguado-Barrera ME, Pacheco-Calleros J, Rodriguez-Padilla C, Cerda-Flores RM, Cortes-Gutierrez EI, Davila-Rodriguez MI (2010) Immunohistochemical analysis of prostate apoptosis response-4 (Par-4) in Mexican women with breast cancer: a preliminary study. Arch Med Res 41(4):261–268PubMedGoogle Scholar
  17. 17.
    Nagai MA, Gerhard R, Salaorni S, Fregnani JH, Nonogaki S, Netto MM, Soares FA (2010) Down-regulation of the candidate tumor suppressor gene PAR-4 is associated with poor prognosis in breast cancer. Int J Oncol 37(1):41–49PubMedGoogle Scholar
  18. 18.
    Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939PubMedGoogle Scholar
  19. 19.
    Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8(3):197–209PubMedGoogle Scholar
  20. 20.
    Karamboulas C, Ailles L (2013) Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta 1830(2):2481–2495PubMedGoogle Scholar
  21. 21.
    Wang J, Pendergast AM (2015) The emerging role of ABL kinases in solid tumors. Trends Cancer 1(2):110–123PubMedPubMedCentralGoogle Scholar
  22. 22.
    Srinivasan D, Sims JT, Plattner R (2008) Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. Oncogene 27(8):1095–1105PubMedGoogle Scholar
  23. 23.
  24. 24.
    Ganguly SS, Fiore LS, Sims JT, Friend JW, Srinivasan D, Thacker MA, Cibull ML, Wang C, Novak M, Kaetzel DM et al (2012) c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression. Oncogene 31(14):1804–1816PubMedGoogle Scholar
  25. 25.
    Ganguly SS, Plattner R (2012) Activation of Abl family kinases in solid tumors. Genes Cancer 3(5–6):414–425PubMedPubMedCentralGoogle Scholar
  26. 26.
    Smith-Pearson PS, Greuber EK, Yogalingam G, Pendergast AM (2010) Abl kinases are required for invadopodia formation and chemokine-induced invasion. J Biol Chem 285(51):40201–40211PubMedPubMedCentralGoogle Scholar
  27. 27.
    Fiore LS, Ganguly SS, Sledziona J, Cibull ML, Wang C, Richards DL, Neltner JM, Beach C, McCorkle JR, Kaetzel DM et al (2014) c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene 33(36):4508–4520PubMedGoogle Scholar
  28. 28.
    Yu T, Chen X, Zhang W, Colon D, Shi J, Napier D, Rychahou P, Lu W, Lee EY, Weiss HL et al (2012) Regulation of the potential marker for intestinal cells, Bmi1, by beta-catenin and the zinc finger protein KLF4: Implications for colon cancer. J Biol Chem 287:3760–3768PubMedGoogle Scholar
  29. 29.
    Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108(6):837–847PubMedGoogle Scholar
  30. 30.
    Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481PubMedGoogle Scholar
  31. 31.
    Collins LC, Botero ML, Schnitt SJ (2005) Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: an analysis of 825 cases. Am J Clin Pathol 123(1):16–20PubMedGoogle Scholar
  32. 32.
    Rhodes J, York RD, Tara D, Tajinda K, Druker BJ (2000) CrkL functions as a nuclear adaptor and transcriptional activator in Bcr-Abl-expressing cells. Exp Hematol 28(3):305–310PubMedGoogle Scholar
  33. 33.
    Kar B, Reichman CT, Singh S, O’Connor JP, Birge RB (2007) Proapoptotic function of the nuclear Crk II adaptor protein. Biochemistry 46(38):10828–10840PubMedGoogle Scholar
  34. 34.
    Ahmad A (2013) Pathways to breast cancer recurrence. ISRN Oncol.  https://doi.org/10.1155/2013/290568 PubMedPubMedCentralGoogle Scholar
  35. 35.
    Goss PE, Chambers AF (2010) Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 10(12):871–877PubMedGoogle Scholar
  36. 36.
    Early Breast Cancer Trialists’ Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717Google Scholar
  37. 37.
    Saphner T, Tormey DC, Gray R (1996) Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14(10):2738–2746PubMedGoogle Scholar
  38. 38.
    Chacon RD, Costanzo MV (2010) Triple-negative breast cancer. Breast Cancer Res 12(Suppl 2):S3PubMedPubMedCentralGoogle Scholar
  39. 39.
    Wangchinda P, Ithimakin S (2016) Factors that predict recurrence later than 5 years after initial treatment in operable breast cancer. World J Surg Oncol 14(1):223PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedGoogle Scholar
  41. 41.
    Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454PubMedGoogle Scholar
  42. 42.
    Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM, Thompson EW (2008) Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis 25(6):629–642PubMedGoogle Scholar
  43. 43.
    Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, Creasap N, Rosol TJ, Robinson ML, Eng C et al (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68(3):937–945PubMedGoogle Scholar
  44. 44.
    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):488–496PubMedGoogle Scholar
  45. 45.
    Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P, Artemov D, Kowalski J, Carraway H, van Diest P et al (2012) Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-alpha. Oncogene 31(27):3223–3234PubMedGoogle Scholar
  46. 46.
    Riaz M, Sieuwerts AM, Look MP, Timmermans MA, Smid M, Foekens JA, Martens JW (2012) High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes. Breast Cancer Res 14(5):R123PubMedPubMedCentralGoogle Scholar
  47. 47.
    van Nes JG, de Kruijf EM, Putter H, Faratian D, Munro A, Campbell F, Smit VT, Liefers GJ, Kuppen PJ, van de Velde CJ et al (2012) Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients. Breast Cancer Res Treat 133(1):49–59PubMedGoogle Scholar
  48. 48.
    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):3241–3246PubMedGoogle Scholar
  49. 49.
    Bradley WD, Koleske AJ (2009) Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts. J Cell Sci 122(Pt 19):3441–3454PubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang JY (2014) The capable ABL: what is its biological function? Mol Cell Biol 34(7):1188–1197PubMedPubMedCentralGoogle Scholar
  51. 51.
    Colicelli J (2010) ABL tyrosine kinases: evolution of function, regulation, and specificity. Sci Signal 3(139):re6PubMedPubMedCentralGoogle Scholar
  52. 52.
    Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70Google Scholar
  53. 53.
    Zhao H, Ou-Yang F, Chen IF, Hou MF, Yuan SS, Chang HL, Lee YC, Plattner R, Waltz SE, Ho SM et al (2010) Enhanced resistance to tamoxifen by the c-ABL proto-oncogene in breast cancer. Neoplasia 12(3):214–223PubMedPubMedCentralGoogle Scholar
  54. 54.
    Weigel MT, Banerjee S, Arnedos M, Salter J, A’Hern R, Dowsett M, Martin LA (2013) Enhanced expression of the PDGFR/Abl signaling pathway in aromatase inhibitor-resistant breast cancer. Ann Oncol 24(1):126–133PubMedGoogle Scholar
  55. 55.
    Greuber EK, Smith-Pearson P, Wang J, Pendergast AM (2013) Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 13(8):559–571PubMedPubMedCentralGoogle Scholar
  56. 56.
    Paulson KE, Rieger-Christ K, McDevitt MA, Kuperwasser C, Kim J, Unanue VE, Zhang X, Hu M, Ruthazer R, Berasi SP et al (2007) Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer. Cancer Res 67(13):6136–6145PubMedGoogle Scholar
  57. 57.
    Debies MT, Gestl SA, Mathers JL, Mikse OR, Leonard TL, Moody SE, Chodosh LA, Cardiff RD, Gunther EJ (2008) Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. J Clin Invest 118(1):51–63PubMedGoogle Scholar
  58. 58.
    Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, Martens JW (2008) Subtypes of breast cancer show preferential site of relapse. Cancer Res 68(9):3108–3114PubMedGoogle Scholar
  59. 59.
    Arnold KM, Pohlig RT, Sims-Mourtada J (2017) Co-activation of Hedgehog and Wnt signaling pathways is associated with poor outcomes in triple negative breast cancer. Oncol Lett 14(5):5285–5292PubMedPubMedCentralGoogle Scholar
  60. 60.
    Yang L, Tang H, Kong Y, Xie X, Chen J, Song C, Liu X, Ye F, Li N, Wang N et al (2015) LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/beta-catenin signaling. Stem Cells 33(10):2913–2924PubMedGoogle Scholar
  61. 61.
    Qureshi A, Pervez S (2010) Allred scoring for ER reporting and it’s impact in clearly distinguishing ER negative from ER positive breast cancers. J Pak Med Assoc 60(5):350–353PubMedGoogle Scholar
  62. 62.
    Mao Y, Zhang N, Xu J, Ding Z, Zong R, Liu Z (2012) Significance of heterogeneous Twist2 expression in human breast cancers. PLoS ONE 7(10):e48178PubMedPubMedCentralGoogle Scholar
  63. 63.
    Zhou S, Sun X, Yu L, Zhou R, Li A, Li M, Yang W (2018) Differential expression and clinical significance of epithelial-mesenchymal transition markers among different histological types of triple-negative breast cancer. J Cancer 9(3):604–613PubMedPubMedCentralGoogle Scholar
  64. 64.
    Hebbar N, Shrestha-Bhattarai T, Rangnekar VM (2013) Par-4 prevents breast cancer recurrence. Breast Cancer Res 15(5):314PubMedPubMedCentralGoogle Scholar
  65. 65.
    Esparza-Lopez J, Ramos-Elias PA, Castro-Sanchez A, Rocha-Zavaleta L, Escobar-Arriaga E, Zentella-Dehesa A, Leon-Rodriguez E, Medina-Franco H, Ibarra-Sanchez Mde J (2016) Primary breast cancer cell culture yields intra-tumor heterogeneous subpopulations expressing exclusive patterns of receptor tyrosine kinases. BMC Cancer 16(1):740PubMedPubMedCentralGoogle Scholar
  66. 66.
    Wang Z, Zhang H, Hou J, Niu J, Ma Z, Zhao H, Liu C (2015) Clinical implications of beta-catenin protein expression in breast cancer. Int J Clin Exp Pathol 8(11):14989–14994PubMedPubMedCentralGoogle Scholar
  67. 67.
    Heiser LM, Sadanandam A, Kuo WL, Benz SC, Goldstein TC, Ng S, Gibb WJ, Wang NJ, Ziyad S, Tong F et al (2012) Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci USA 109(8):2724–2729PubMedGoogle Scholar
  68. 68.
    Bryce NS, Reynolds AB, Koleske AJ, Weaver AM (2013) WAVE2 regulates epithelial morphology and cadherin isoform switching through regulation of Twist and Abl. PLoS ONE 8(5):e64533PubMedPubMedCentralGoogle Scholar
  69. 69.
    Amin H, Nayak D, Ur Rasool R, Chakraborty S, Kumar A, Yousuf K, Sharma PR, Ahmed Z, Sharma N, Magotra A et al (2016) Par-4 dependent modulation of cellular beta-catenin by medicinal plant natural product derivative 3-azido Withaferin A. Mol Carcinog 55(5):864–881PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Markey Cancer CenterUniversity of KentuckyLexingtonUSA
  2. 2.Department of Internal Medicine, Division of Medical Oncology, College of MedicineUniversity of KentuckyLexingtonUSA
  3. 3.Department of Pharmacology and Nutritional Sciences, College of MedicineUniversity of KentuckyLexingtonUSA
  4. 4.Department of Molecular and Cellular Biochemistry, College of MedicineUniversity of KentuckyLexingtonUSA
  5. 5.Department of Radiation Medicine, College of MedicineUniversity of KentuckyLexingtonUSA
  6. 6.Department of Pathology and Laboratory Medicine, College of MedicineUniversity of KentuckyLexingtonUSA
  7. 7.Department of Biostatistics, College of Public HealthUniversity of KentuckyLexingtonUSA
  8. 8.Department of Epidemiology, College of Public HealthUniversity of KentuckyLexingtonUSA
  9. 9.Markey Cancer CenterUniversity of KentuckyLexingtonUSA

Personalised recommendations

Cite article

Buy options