Skip to main content

Advertisement

SpringerLink
Log in

Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

Drug resistance is a major obstacle to the successful chemotherapy. Several ATP-binding cassette (ABC) transporters including ABCB1, ABCC1 and ABCG2 have been known to be important mediators of chemoresistance. Using oligonucleotide microarrays (HG-U133 Plus 2.0; Affymetrix), we analyzed the ABC transporter gene expression profiles in breast cancer patients who underwent sequential weekly paclitaxel/FEC (5-fluorouracil, epirubicin and cyclophosphamide) neoadjuvant chemotherapy. We compared the ABC transporter expression profile between two classes of pretreatment tumor samples divided by the patients’ pathological response to neoadjuvant chemotherapy (residual disease [RD] versus pathologic complete response [pCR]) ABCB3, ABCC7 and ABCF2 showed significantly high expression in the pCR. Several ABC transporters including ABCC5, ABCA12, ABCA1 ABCC13, ABCB6 and ABCC11 showed significantly increased expression in the RD (p<0.05). We evaluated the feasibility of developing a multigene predictor model of pathologic response to neoadjuvant chemotherapy using gene expression profiles of ABC transporters. The prediction error was evaluated by leave-one-out cross-validation (LOOCV). A multigene predictor model with the ABC transporters differentially expressed between the two classes (p≤0.003) showed an average 92.8% of predictive accuracy (95% CI, 88.0–97.4%) with a 93.2% (95% CI, 85.2–100%) positive predictive value for pCR, a 93.6% (95% CI, 87.8–99.4%) negative predictive value, a sensitivity of 88.1%(95% CI, 76.8–99.4%), and a specificity of 95.9% (91.1% CI, 87.8–100%). Our results suggest that several ABC transporters in human breast cancer cells may affect the clinical response to neoadjuvant chemotherapy, and transcriptional profiling of these genes may be useful to predict the pathologic response to sequential weekly paclitaxel/FEC in breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, Gottesman MM: Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplificationScience232: 643–645, 1986

    Article  PubMed  CAS  Google Scholar 

  2. Roninson IB, Chin JE, Choi KG, Gros P, Housman DE, Fojo A, Shen DW, Gottesman MM, Pastan I: Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cellsProc Natl Acad Sci USA83: 4538–4542, 1986

    Article  PubMed  CAS  Google Scholar 

  3. Rosenberg MF, Mao Q, Holzenburg A, Ford RC, Deeley RG, Cole SP: The structure of the multidrug resistance protein 1 (MRP1/ABCC1). crystallization and single-particle analysisJ Biol Chem276: 16,076–16,082, 2001

    CAS  Google Scholar 

  4. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD: A multidrug resistance transporter from human MCF-7 breast cancer cellsProc Natl Acad Sci USA95: 15,665–15,670, 1998

    Article  CAS  Google Scholar 

  5. Mechetner E, Kyshtoobayeva A, Zonis S, Kim H, Stroup R, Garcia R, Parker RJ, Fruehauf JP: Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicinClin Cancer Res4: 389–398, 1998

    PubMed  CAS  Google Scholar 

  6. Candeil L, Gourdier I, Peyron D, Vezzio N, Copois V, Bibeau F, Orsetti B, Scheffer GL, Ychou M, Khan QA, Pommier Y, Pau B, Martineau P, Del Rio M: ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastasesInt J Cancer109: 848–854, 2004

    Article  PubMed  CAS  Google Scholar 

  7. Salmon SE, Grogan TM, Miller T, Scheper R, Dalton WS: Prediction of doxorubicin resistance in vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein stainingJ Natl Cancer Inst81: 696–701, 1989

    Article  PubMed  CAS  Google Scholar 

  8. Nakamura Y, Oka M, Soda H, Shiozawa K, Yoshikawa M, Itoh A, Ikegami Y, Tsurutani J, Nakatomi K, Kitazaki T, Doi S, Yoshida H, Kohno S: Gefitinib (“Iressa”, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistanceCancer Res65: 1541–1546, 2005

    Article  PubMed  CAS  Google Scholar 

  9. Gillet JP, Efferth T, Steinbach D, Hamels J, de Longueville F, Bertholet V, Remacle J: Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genesCancer Res64: 8987–8993, 2004

    Article  PubMed  CAS  Google Scholar 

  10. Szakacs G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, Reinhold W, Guo Y, Kruh GD, Reimers M, Weinstein JN, Gottesman MM: Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cellsCancer Cell6: 129–137, 2004

    Article  PubMed  CAS  Google Scholar 

  11. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B: Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18J Natl Cancer InstMonogr: 96–102, 2001

    Google Scholar 

  12. Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extractionAnal Biochem162: 156–159, 1987

    Article  PubMed  CAS  Google Scholar 

  13. Radmacher MD, McShane LM, Simon R: A paradigm for class prediction using gene expression profilesJ Comput Biol9: 505–511, 2002

    Article  PubMed  CAS  Google Scholar 

  14. Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M, Ladd C, Reich M, Latulippe E, Mesirov JP, Poggio T, Gerald W, Loda M, Lander ES, Golub TR: Multiclass cancer diagnosis using tumor gene expression signaturesProc Natl Acad Sci USA98: 15,149–15,154, 2001

    Article  CAS  Google Scholar 

  15. Simon R, Radmacher MD, Dobbin K, McShane LM: Pitfalls in the use of DNA microarray data for diagnostic and prognostic classificationJ Natl Cancer Inst95: 14–18, 2003

    Article  PubMed  CAS  Google Scholar 

  16. Ambroise C, McLachlan GJ: Selection bias in gene extraction on the basis of microarray gene-expression dataProc Natl Acad Sci USA99: 6562–6566, 2002

    Article  PubMed  CAS  Google Scholar 

  17. Pratt S, Shepard RL, Kandasamy RA, Johnston PA, Perry W, III, Dantzig AH: The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolitesMol Cancer Ther4: 855–863, 2005

    Article  PubMed  CAS  Google Scholar 

  18. Momburg F, Hammerling GJ: Generation and TAP-mediated transport of peptides for major histocompatibility complex class I moleculesAdv Immunol68: 191–256, 1998

    Article  PubMed  CAS  Google Scholar 

  19. Singal DP, Ye M, Ni J, Snider DP: Markedly decreased expression of TAP1 and LMP2 genes in HLA class I-deficient human tumor cell linesImmunol Lett50: 149–154, 1996

    Article  PubMed  CAS  Google Scholar 

  20. Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B: Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcomeClin Cancer Res11: 2552–2560, 2005

    Article  PubMed  CAS  Google Scholar 

  21. Cresswell AC, Sisley K, Laws D, Parsons MA, Rennie IG, Murray AK: Reduced expression of TAP-1 and TAP-2 in posterior uveal melanoma is associated with progression to metastatic diseaseMelanoma Res11: 275–281, 2001

    Article  PubMed  CAS  Google Scholar 

  22. Atkins D, Breuckmann A, Schmahl GE, Binner P, Ferrone S, Krummenauer F, Storkel S, Seliger B: MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinomaInt J Cancer109: 265–273, 2004

    Article  PubMed  CAS  Google Scholar 

  23. Allikmets R, Gerrard B, Hutchinson A, Dean M: Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags databaseHum Mol Genet5: 1649–1655, 1996

    Article  PubMed  CAS  Google Scholar 

  24. Wielinga P, Hooijberg JH, Gunnarsdottir S, Kathmann I, Reid G, Zelcer N, van der Born K, de Haas M, van der Heijden I, Kaspers G, Wijnholds J, Jansen G, Peters G, Borst P: The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolatesCancer Res65: 4425–4430, 2005

    Article  PubMed  CAS  Google Scholar 

  25. Hu XF, Slater A, Rischin D, Kantharidis P, Parkin JD, Zalcberg J: Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cellline Br J Cancer79: 831–837, 1999

    Article  PubMed  CAS  Google Scholar 

  26. Mealey KL, Barhoumi R, Burghardt RC, Safe S, Kochevar DT: Doxycycline induces expression of P glycoprotein in MCF-7 breast carcinoma cellsAntimicrob Agents Chemother46: 755–761, 2002

    Article  PubMed  CAS  Google Scholar 

  27. Filipits M, Pohl G, Rudas M, Dietze O, Lax S, Grill R, Pirker R, Zielinski CC, Hausmaninger H, Kubista E, Samonigg H, Jakesz R: Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study GroupJ Clin Oncol23: 1161–1168, 2005

    Article  PubMed  CAS  Google Scholar 

  28. Schmitz G, Langmann T: Structure, function and regulation of the ABC1 gene productCurr Opin Lipidol12: 129–140, 2001

    Article  PubMed  CAS  Google Scholar 

  29. Schmitz G, Kaminski WE, Porsch-Ozcurumez M, Klucken J, Orso E, Bodzioch M, Buchler C, Drobnik W: ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism?Pathobiology67: 236–240, 1999

    Article  PubMed  CAS  Google Scholar 

  30. Yabuuchi H, Takayanagi S, Yoshinaga K, Taniguchi N, Aburatani H, Ishikawa T: ABCC13, an unusual truncated ABC transporter, is highly expressed in fetal human liverBiochem Biophys Res Commun299: 410–417, 2002

    Article  PubMed  CAS  Google Scholar 

  31. Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, Kruh GD: MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2′,3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenineJ Biol Chem278: 29,509–29,514, 2003

    CAS  Google Scholar 

  32. Mitsuhashi N, Miki T, Senbongi H, Yokoi N, Yano H, Miyazaki M, Nakajima N, Iwanaga T, Yokoyama Y, Shibata T, Seino S: MTABC3, a novel mitochondrial ATP-binding cassette protein involved in iron homeostasisJ Biol Chem275: 17,536–17,540, 2000

    CAS  Google Scholar 

  33. Yasui K, Mihara S, Zhao C, Okamoto H, Saito-Ohara F, Tomida A, Funato T, Yokomizo A, Naito S, Imoto I, Tsuruo T, Inazawa J: Alteration in copy numbers of genes as a mechanism for acquired drug resistanceCancer Res64: 1403–1410, 2004

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partially supported by funds for the Third Term Comprehensive 10-Year Strategy for Cancer Control and a Grant-in-Aid for Scientific Research and for Health and Labor Science Research Grants, Research on Advanced Medical Technology, H14-Toxico-007. We are grateful to Tokuzo Arao, Tsutomu Ohta, and Takayuki Kinoshita, for their contribution to the article and assistance in collection of clinical data. Analyses were carried out using BRB ArrayTools developed by Dr. Richard Simon and Amy Peng Lam.

Author information

Authors and Affiliations

  1. Shien Lab, National Cancer Center Hospital, Tokyo, Japan

    Sarah Park, Tatsu Shimoyama, Masayuki Takeda & Kazuto Nishio

  2. Breast and Medical Oncology National Cancer Center Hospital, Tokyo, Japan

    Chikako Shimizu, Masashi Ando, Tsutomu Kohno, Noriyuki Katsumata & Yasuhiro Fujiwara

  3. Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan

    Yoon-Koo Kang & Kazuto Nishio

  4. Center for Medical Genomics, National Cancer Center Research Institute, Tokyo, Japan

    Sarah Park

  5. Division of Hematology–Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

    Kazuto Nishio

  6. Shien Lab, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, 104-0045, Tokyo, Japan

    Kazuto Nishio

Authors
  1. Sarah Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chikako Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsu Shimoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masayuki Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masashi Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tsutomu Kohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Noriyuki Katsumata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoon-Koo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuto Nishio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yasuhiro Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kazuto Nishio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, S., Shimizu, C., Shimoyama, T. et al. Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat 99, 9–17 (2006). https://doi.org/10.1007/s10549-006-9175-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9175-2

Keywords

Search

Navigation