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Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy

  • Preclinical study
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Abstract

Purpose

Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms.

Methods

We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC.

Results

The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients.

Conclusion

KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.

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Abbreviations

ABCB1/MDR1:

Multidrug resistance 1 encoded by the gene ABCB1

ABCC1/MRP1:

Multidrug resistance protein 1 encoded by the gene ABCC1

ABCG2/BCRP1:

Breast cancer resistance protein encoded by the gene ABCG2

Bcl2:

B-cell lymphoma 2

CI:

Confidence interval

CR:

Complete response

DFS:

Disease-free survival

LI:

Labeling index

NAC:

Neoadjuvant chemotherapy

OR:

Odd ratio

OS:

Overall survival

p53:

Tumor protein 53

pCR:

Pathologic complete response

PD:

Progressive disease

PR:

Partial response

PTEN:

Phosphatase and tensin homolog

RD:

Residual disease

SD:

Stable disease

TNBC:

Triple-negative breast cancer

TNM:

Tumor, node, metastasis

TopoIIα:

Topoisomerase IIα

References

  1. Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281

    Article  Google Scholar 

  2. Wu K, Yang Q, Liu Y, Wu A, Yang Z (2014) Meta-analysis on the association between pathologic complete response and triple-negative breast cancer after neoadjuvant chemotherapy. World J Surg Oncol 12:95. https://doi.org/10.1186/1477-7819-12-95

    Article  PubMed  PubMed Central  Google Scholar 

  3. Martin M, Romero A, Cheang MCU, Lopez Garcıa-Asenjo JU, Garcıa-Saenz JA, Oliva B, Roman JM, He X, Casado A, de la Torre J, Furio J, Puente J, Caldes T, Vidart JA, Lopez-Tarruella S, Diaz-Rubio E, Perou CM (2011) Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat 128:127–136

    Article  CAS  Google Scholar 

  4. Wahba HA, El-Hadaad HA (2015) Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med 12(2):106–116

    PubMed  PubMed Central  CAS  Google Scholar 

  5. Székely B, Silber AL, Pusztai L (2017) New therapeutic strategies for triple-negative breast cancer. Oncology 31(2):130–137

    Google Scholar 

  6. Zhang LH, Yang AJ, Wang M, Liu W, Wang CY, Xie XF, Chen X, Dong JF, Li M (2016) Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells. Apoptosis 21(4):473–488

    Google Scholar 

  7. Yamada A, Ishikawa T, Ota I, Kimura M, Shimizu D, Tanabe M, Chishima T, Sasaki T, Ichikawa Y, Morita S, Yoshiura K, Takabe K, Endo I (2013) High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival. Breast Cancer Res Treat 137(3):773–782

    Article  CAS  Google Scholar 

  8. Xu H, Eirew P, Mullaly SC, Aparicio S (2014) The omics of triple-negative breast cancers. Clin Chem 60(1):122–133

    Article  CAS  Google Scholar 

  9. Florea AM, Busselberg D (2013) Breast cancer and possible mechanisms of therapy resistance. J Local Glob Health Sci. https://doi.org/10.5339/jlghs

    Article  Google Scholar 

  10. O’Reilly EA, Gubbins L, Sharma S, Tully R, Ho Zhing Guang M, Weiner-Gorzel W, McCaffrey J, Harrison M, Furlong F, Kell M, McCanna A (2015) The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin 3:257–275

    Article  Google Scholar 

  11. Bouchalova K, Cizkova M, Cwiertka K, Trojanec R, Hajduch M (2009) Triple negative breast cancer-current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 153(1):13–17

    Article  Google Scholar 

  12. Balko JM, Giltnane JM, Wang K, Schwarz LJ (2014) Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4(2):232–245

    Article  CAS  Google Scholar 

  13. Lonning PE, Knappskog S (2013) Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers. Oncogene 32(46):5315–5330

    Article  CAS  Google Scholar 

  14. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4):387–391

    Article  CAS  Google Scholar 

  15. Davis SL, Eckhardt SG, Tentler JJ, Diamond JR (2014) Triple-negative breast cancer: bridging the gap from cancer genomics to predictive biomarkers. Ther Adv Med Oncol 6(3):88–100

    Article  CAS  Google Scholar 

  16. Lehmann BD, Pietenpol JA (2014) Identification and use of biomarkers in treatment strategies for triple negative breast cancer subtypes. J Pathol 232(2):142–150

    Article  Google Scholar 

  17. Guestini F, McNamara KM, Ishida T, Sasano H (2016) Triple negative breast cancer chemosensitivity and chemoresistance: current advances in biomarkers identification. Exp Opin Ther Targets 20(6):705–720

    Article  CAS  Google Scholar 

  18. Yadav BS, Chanana P, Jhamb S (2015) Biomarkers in triple negative breast cancer: a review. World J Clin Oncol 6(6):252–263

    Article  Google Scholar 

  19. Fleisher B, Clarke C, Ait-Oudhia S (2016) Current advances in biomarkers for targeted therapy in triple-negative breast cancer. Breast Cancer 8:183–197

    Google Scholar 

  20. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292

    Article  CAS  Google Scholar 

  21. Rivera E, Gomez H (2010) Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone. Breast Cancer Res 12(2):S2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ossovskaya V, Wang Y, Budoff A, Xu Q, Lituev A, Potapova O, Vansant G, Monforte J, Daraselia N (2011) Exploring molecular pathways of triple-negative breast cancer. Genes Cancer 2(9):870–879

    Article  CAS  Google Scholar 

  23. Lips EH, Michaut M, Hoogstraat M, Mulder L, Besselink NJM, Koudijs MJ, Cuppen E, Voest EE, Bernards R, Nederlof PM, Wesseling J, Rodenhuis S, Wessels LFA (2015) Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response. Breast Cancer Res 17(1):134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Chen Y-H, Hancock BA, Solzak JP, Brinza D, Scafe C, Miller KD, Radovich M (2017) Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. NPJ Breast Cancer 3(1):24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Santuario-Facio SK, Cardona-Huerta S, Perez-Paramo YX, Trevino V, Hernandez-Cabrera F, Rojas-Martinez A, Uscanga-Perales G, Martinez-Rodriguez JL, Martinez-Jacobo L, Padilla-Rivas G et al (2017) A new gene expression signature for triple-negative breast cancer using frozen fresh tissue before neoadjuvant chemotherapy. Mol Med 23:101–111

    Article  CAS  Google Scholar 

  26. Wein L, Loi S (2017) Mechanisms of resistance of chemotherapy in early-stage triple negative breast cancer (TNBC). Breast 34(Suppl 1):S27–S30

    Google Scholar 

  27. Bareche Y, Venet D, Ignatiadis M, Aftimos P, Piccart M, Rothe F, Sotiriou C (2018) Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis. Ann Oncol 29:895–902

    Article  Google Scholar 

  28. Kim T, Han W, Kim MK, Lee JW, Kim J, Ahn SK, Lee H-B, Moon H-G, Lee K-H, Kim T-Y et al (2015) Predictive significance of p53, Ki-67, and Bcl-2 expression for pathologic complete response after neoadjuvant chemotherapy for triple-negative breast cancer. J Breast Cancer 18(1):16–21

    Google Scholar 

  29. Wang W, Wu J, Zhang P, Fei X, Zong Y, Chen X, Huang O, He J-R, Chen W, Li Y et al (2016) Prognostic and predictive value of Ki-67 in triple-negative breast cancer. Oncotarget 7(21):31079–31087

    Google Scholar 

  30. Elnemr GM, El-Rashidy AH, Osman AH, Issa LF, Abbas OA, Al-Zahrani AS, El-Seman SM, Mohammed AA, Hassan AA (2016) Response of triple negative breast cancer to neoadjuvant chemotherapy: correlation between Ki-67 expression and pathological response. Asian Pac J Cancer Prev 17(2):807–813

    Article  Google Scholar 

  31. Nakashoji A, Matsui A, Nagayama A, Iwata Y, Sasahara M, Murata Y (2017) Clinical predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer. Oncol Lett 14(4):4135–4141

    Article  CAS  Google Scholar 

  32. Nogi H, Uchida KEN, Kamio M, Kato K, Toriumi Y, Akiba T, Morikawa T, Suzuki M, Kobayashi T, Takeyama H (2016) Triple-negative breast cancer exhibits a favorable response to neoadjuvant chemotherapy independent of the expression of Topoisomerase IIα. Mol Clin Oncol 4(3):383–389

    Google Scholar 

  33. Li XY, Mu L, Feng J (2016) Topoisomerase IIα and BRCA1 expression as predictive factors for anthracycline-based adjuvant chemotherapy response and prognosis in triple-negative breast cancers. Int J Clin Exp Pathol 9(9):9249–9258

    Google Scholar 

  34. Ignatiadis M, Singhal SK, Desmedt C, Haibe-Kains B, Criscitiello C, Andre F, Loi S, Piccart M, Michiels S, Sotiriou C (2012) Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J Clin Oncol 30(16):1996–2004

    Article  CAS  Google Scholar 

  35. Duffy MJ, Synnott NC, Crown J (2018) Mutant p53 in breast cancer: potential as a therapeutic target and biomarker. Breast Cancer Res Treat 170:213. https://doi.org/10.1007/s10549-018-4753-7

    Article  PubMed  CAS  Google Scholar 

  36. Abdel-Fatah TM, Perry C, Dickinson P, Ball G, Moseley P, Madhusudan S, Ellis IO, Chan SY (2013) Bcl2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Ann Oncol 24(11):2801–2807

    Article  Google Scholar 

  37. Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y (2013) 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 138(1):81–90

    Article  CAS  Google Scholar 

  38. Yamashita N, Tokunaga E, Kitao H, Hisamatsu Y, Taketani K, Akiyoshi S, Okada S, Aishima S, Morita M, Maehara Y (2013) Vimentin as a poor prognostic factor for triple-negative breast cancer. J Cancer Res Clin Oncol 139(5):739–746

    Article  CAS  Google Scholar 

  39. Wang L, Jiang Z, Sui M, Shen J, Xu C, Fan W (2009) The potential biomarkers in predicting pathologic response of breast cancer to three different chemotherapy regimens: a case control study. BMC Cancer 9:226–226

    Google Scholar 

  40. Kovalev AA, Tsvetaeva DA, Grudinskaja TV (2013) Role of ABC-cassette transporters (MDR1, MRP1, BCRP) in the development of primary and acquired multiple drug resistance in patients with early and metastatic breast cancer. Exp Oncol 35(4):287–290

    Google Scholar 

  41. Delou JMdA, Vignal GM, Índio-do-Brasil V, Accioly MTdS, da Silva TSL, Piranda DN, Sobral-Leite M, de Carvalho MA, Capella MAM, Vianna-Jorge R (2017) Loss of constitutive ABCB1 expression in breast cancer associated with worse prognosis. Breast Cancer 9:415–428

    Google Scholar 

  42. Eisenhauera EA, Therasseb P, Bogaertsc J, Schwartzd LH, Sargente D, Fordf R, Danceyg J, Arbuckh S, Gwytheri S, Mooneyg M, Rubinsteing L, Shankarg L, Doddg L, Kaplanj R, Lacombec D, Verweijk J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Google Scholar 

  43. Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204(3):216–237

    Article  CAS  Google Scholar 

  44. Kim B, Fatayer H, Hanby AM, Horgan K, Perry SL, Valleley EM, Verghese ET, Williams BJ, Thorne JL, Hughes TA (2013) Neoadjuvant chemotherapy induces expression levels of breast cancer resistance protein that predict disease-free survival in breast cancer. PLoS ONE 8(5):e62766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Collina F, Di Bonito M, Li Bergolis V, De Laurentiis M, Vitagliano C, Cerrone M, Nuzzo F, Cantile M, Botti G (2015) Prognostic value of cancer stem cells markers in triple-negative breast cancer. Biomed Res Int 2015:158682

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Chen Z-S, Tiwari AK (2011) Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J 278(18):3226–3245

    Article  CAS  Google Scholar 

  47. Kathawala RJ, Gupta P, Ashby CR, Chen ZS (2015) The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Updates 18:1–17

    Article  Google Scholar 

  48. Zhang L-h, Yang A-j, Wang M, Liu W, Wang C-y, Xie X-f, Chen X, Dong J-f, Li M (2016) Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells. Apoptosis 21(4):473–488

    Google Scholar 

  49. Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (2016) Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS ONE 11(6):e0157368

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Jang MH, Kim HJ, Kim EJ, Chung YR, Park SY (2015) Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome. Hum Pathol 46(9):1267–1274

    Article  CAS  Google Scholar 

  51. Tawfik K, Kimler BF, Davis MK, Fan F, Tawfik O (2012) Prognostic significance of Bcl-2 in invasive mammary carcinomas: a comparative clinicopathologic study between “triple-negative” and non-“triple-negative” tumors. Hum Pathol 43(1):23–30

    Article  CAS  Google Scholar 

  52. Hwang KT, Woo JW, Shin HC, Kim HS, Ahn SK, Moon HG, Han W, Park IA, Noh DY (2012) Prognostic influence of BCL2 expression in breast cancer. Int J Cancer 131(7):E1109–E1119

    Article  CAS  Google Scholar 

  53. Vargas-Roig LM, Cuello-Carrión FD, Fernández-Escobar N, Daguerre P, Leuzzi M, Ibarra J, Gago FE, Nadin SB, Ciocca DR (2008) Prognostic value of Bcl-2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy. Mol Oncol 2(1):102–111

    Article  Google Scholar 

  54. Chen W, Dong J, Haiech J, Kilhoffer MC, Zeniou M (2016) Cancer stem cell quiescence and plasticity as major challenges in cancer therapy. Stem Cells Int 2016. https://doi.org/10.1155/2016/1740936

    Article  PubMed  PubMed Central  Google Scholar 

  55. Guestini F, McNamara KM, Sasano H (2017) The use of chemosensitizers to enhance the response to conventional therapy in triple-negative breast cancer patients. Breast Cancer Manag 6(4):127–131

    Article  CAS  Google Scholar 

  56. Hu Y, Yague E, Zhao J, Wang L, Bai J, Yang Q, Pan T, Zhao H, Liu J, Zhang J (2018) Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer. Cancer Lett 423:47–59

    Article  CAS  Google Scholar 

  57. Yndestad S, Austreid E, Knappskog S, Chrisanthar R, Lilleng PK, Lonning PE, Eikesdal HP (2017) High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function. Breast Cancer Res Treat 163(1):177–190

    Article  CAS  Google Scholar 

  58. Brandmaier A, Hou SQ, Shen WH (2017) Cell cycle control by PTEN. J Mol Biol 429(15):2265–2277

    Article  CAS  Google Scholar 

  59. Wang X, Jiang X (2008) Post-translational regulation of PTEN. Oncogene 27(41):5454–5463

    Article  CAS  Google Scholar 

  60. Bermúdez Brito M, Goulielmaki E, Papakonstanti EA (2015) Focus on PTEN regulation. Front Oncol 5:166

    Article  PubMed  PubMed Central  Google Scholar 

  61. Iqbal J, Thike AA, Cheok PY, Tse GM, Tan PH (2012) Insulin growth factor receptor-1 expression and loss of PTEN protein predict early recurrence in triple-negative breast cancer. Histopathology 61(4):652–659

    Article  Google Scholar 

  62. Inanc M, Ozkan M, Karaca H, Berk V, Bozkurt O, Duran AO, Ozaslan E, Akgun H, Tekelioglu F, Elmali F (2014) Cytokeratin 5/6, c-Met expressions, and PTEN loss prognostic indicators in triple-negative breast cancer. Med Oncol 31(1):801

    Article  PubMed  CAS  Google Scholar 

  63. Beg S, Siraj AK, Prabhakaran S, Jehan Z, Ajarim D, Al-Dayel F, Tulbah A, Al-Kuraya KS (2015) Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer. Breast Cancer Res Treat 151(3):541–553

    Article  CAS  Google Scholar 

  64. Li S, Shen Y, Wang M, Yang J, Lv M, Li P, Chen Z, Yang J (2017) Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis. Oncotarget 8(19):32043–32054

    Google Scholar 

  65. Fouque A, Jean M, Weghe PV, Legembre P (2016) Review of PI3K/mTOR inhibitors entering clinical trials to treat triple negative breast cancers. Recent Pat Anticancer Drug Discov 11(3):283–296

    Article  CAS  Google Scholar 

  66. Costa RLB, Han HS, Gradishar WJ (2018) Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-018-4697-y

    Article  PubMed  Google Scholar 

  67. Massihnia D, Galvano A, Fanale D, Perez A, Castiglia M, Incorvaia L, Listi A, Rizzo S, Cicero G, Bazan V, Castorina S, Russo A (2016) Triple negative breast cancer: shedding light onto the role of PI3K/Akt/mTOR pathway. Oncotarget 7(37):60712–60722

    Article  Google Scholar 

  68. Kang X, Song C, Du X, Zhang C, Liu Y, Liang L, He J, Lamb K, Shen WH, Yin Y (2015) PTEN stabilizes TOP2A and regulates the DNA decatenation. Sci Rep 5:17873

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Yuan L, Lv Y, Li H, Gao H, Song S, Zhang Y, Xing G, Kong X, Wang L, Li Y, Zhou T, Gao D, Xiao ZX, Yin Y, Wei W, He F, Zhang L (2015) Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis. Nat Cell Biol 17:1169

    Article  PubMed  CAS  Google Scholar 

  70. Fielding AB, Concannon M, Darling S, Rusilowicz-Jones EV, Sacco JJ, Prior IA, Clague MJ, Urbé S, Coulson JM (2018) The deubiquitylase USP15 regulates Topoisomerase II alpha to maintain genome integrity. Oncogene. https://doi.org/10.1038/s41388-017-0092-0

    Article  PubMed  PubMed Central  Google Scholar 

  71. Millis SZ, Gatalica Z, Winkler J, Vranic S, Kimbrough J, Reddy S, O’Shaughnessy JA (2015) Predictive biomarker profiling of > 6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications. Clin Breast Cancer 15(6):473–481

    Article  CAS  Google Scholar 

  72. Zeichner SB, Terawaki H, Gogineni K (2016) A review of systemic treatment in metastatic triple-negative breast cancer. Breast Cancer 10:25–36

    Google Scholar 

  73. Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, Lee SH, Han W, Kim DW, Kim TY, Park IA, Noh DY, Heo DS, Bang YJ (2011) Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res 13(2):R22

    Article  PubMed  PubMed Central  Google Scholar 

  74. Li XR, Liu M, Zhang YJ, Wang JD, Zheng YQ, Li J, Ma B, Song X (2011) CK5/6, EGFR, Ki-67, cyclin D1, and nm23-H1 protein expressions as predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer patients. Med Oncol 28(Suppl 1):S129–S134

    Google Scholar 

  75. Tan QX, Qin QH, Yang WP, Mo QG, Wei CY (2014) Prognostic value of Ki67 expression in HR-negative breast cancer before and after neoadjuvant chemotherapy. Int J Clin Exp Pathol 7(10):6862–6870

    Google Scholar 

  76. Tian M, Zhong Y, Zhou F, Xie C, Zhou Y, Liao Z (2015) Effect of neoadjuvant chemotherapy in patients with triple-negative breast cancer: a meta-analysis. Oncol Lett 9(6):2825–2832

    Article  CAS  Google Scholar 

  77. Pan Y, Yuan Y, Liu G, Wei Y (2017) P53 and Ki-67 as prognostic markers in triple-negative breast cancer patients. PLoS ONE 12(2):e0172324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Wang J, Xu B, Yuan P, Zhang P, Li Q, Ma F, Fan Y (2012) TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy. Breast Cancer Res Treat 135(2):531–537

    Article  CAS  Google Scholar 

  79. Bravaccini S, Rocca A, Bronte G (2018) Is Ki67 still a powerful ally in predicting the clinical benefit of anthracyclines for the adjuvant treatment of early breast cancer? Breast Cancer Res Treat 168:767–768

    Article  CAS  Google Scholar 

  80. Rossi L, Laas E, Mallon P, Vincent-Salomon A, Guinebretiere JM, Lerebours F, Rouzier R, Pierga JY, Reyal F (2015) Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma. Br J Cancer 113:996

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Mueller RE, Parkes RK, Andrulis I, O’Malley FP (2004) Amplification of the TOP2A gene does not predict high levels of Topoisomerase II alpha protein in human breast tumor samples. Genes Chromosom Cancer 39:288–297

    Article  CAS  Google Scholar 

  82. Khan F, Esnakula A, Ricks-Santi LJ, Zafar R, Kanaan Y, Naab T (2018) Loss of PTEN in high grade advanced stage triple negative breast ductal cancers in African American women. Pathology 214(5):673–678

    Google Scholar 

  83. Dillon LM, Miller TW (2014) Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets 15(1):65–79

    Article  CAS  Google Scholar 

  84. Darb-Esfahani S, Denkert C, Stenzinger A, Salat C, Sinn B, Schem C, Endris V, Klare P, Schmitt W, Blohmer J-U et al (2016) Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy. Oncotarget 7(42):67686–67698

    Article  Google Scholar 

  85. Yamashita H, Toyama T, Nishio M, Ando Y, Hamaguchi M, Zhang Z, Kobayashi S, Fujii Y, Iwase H (2006) p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer. Breast Cancer Res 8(4):R48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Varga Z, Cassoly E, Li Q, Oehlschlegel C, Tapia C, Lehr HA, Klingbiel D, Thürlimann B, Ruhstaller T (2015) Standardization for Ki-67 assessment in moderately differentiated breast cancer. A retrospective analysis of the SAKK 28/12 study. PLoS ONE 10(4):e0123435

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Biesaga B, Niemiec J, Ziobro M (2014) BCL-2, Topoisomerase IIα, microvessel density and prognosis of early advanced breast cancer patients after adjuvant anthracycline-based chemotherapy. J Cancer Res Clin Oncol 140:2009–2019

    Article  CAS  Google Scholar 

  88. Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA, Burgues O, Lluch AM, Chen H, Hortobagyi GN, Mills GB, Meric-Bernstam F (2011) PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 10(6):1093–1101

    Article  CAS  Google Scholar 

  89. Britton KM, Eyre R, Harvey IJ, Stemke-Hale K, Browell D, Lennard TWJ, Meeson AP (2012) Breast cancer, side population cells and ABCG2 expression. Cancer Lett. https://doi.org/10.1016/j.canlet.2012.1003.1041

    Article  PubMed  PubMed Central  Google Scholar 

  90. Soini Y, Jarvinen K, Kaarteenaho Wiik R, Kinnula V (2001) The expression of P-glycoprotein and multidrug resistance proteins 1 and 2 (MRP1 and MRP2) in human malignant mesothelioma. Ann Oncol 12:1239–1245

    Article  Google Scholar 

Download references

Acknowledgements

The author Fouzia Guestini work was supported by the Japanese Government Ministry of Education, Culture, Sports, Science, and Technology (MEXT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Authors and Affiliations

  1. Tohoku University, Sendai, Japan

    Fouzia Guestini, Katsuhiko Ono, Minoru Miyashita, Takanori Ishida, Noriaki Ohuchi, Saki Nakagawa, Hironobu Sasano & Keely May McNamara

  2. Tohoku Kousai Hospital, Sendai, Japan

    Hisashi Hirakawa

  3. Nahanishi Clinic, Okinawa, Japan

    Kentaro Tamaki

  4. Sagara Hospital, Kagoshima, Japan

    Yasuyo Ohi, Yoshiaki Rai & Yasuaki Sagara

Authors
  1. Fouzia Guestini
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  2. Katsuhiko Ono
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  3. Minoru Miyashita
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  4. Takanori Ishida
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  5. Noriaki Ohuchi
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  6. Saki Nakagawa
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  7. Hisashi Hirakawa
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  8. Kentaro Tamaki
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  9. Yasuyo Ohi
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  10. Yoshiaki Rai
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  11. Yasuaki Sagara
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  12. Hironobu Sasano
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  13. Keely May McNamara
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Corresponding author

Correspondence to Keely May McNamara.

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Guestini, F., Ono, K., Miyashita, M. et al. Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy. Breast Cancer Res Treat 173, 275–288 (2019). https://doi.org/10.1007/s10549-018-4985-6

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  • DOI: https://doi.org/10.1007/s10549-018-4985-6

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