Skip to main content

Advertisement

SpringerLink
Log in

Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Chemotherapy is not only important but also necessary for the patient of breast cancer. Breast cancer resistance protein (BCRP), an atypical drug efflux pump, mediates multidrug resistance in breast cancer. The aim of this study is to search new substrate of BCRP. The result will guide the drug selection of chemotherapy in BCRP-positive breast cancer.

Methods

PA317/Tet-on/TRE-BCRP cell induced with doxycycline was used to screen the possible substrates of BCRP by MTT assay. The suspicious substrate [5-fluorouracil (5-Fu)] was further confirmed in PA317 and breast cancer cell MCF-7 by HLCP, apoptosis assay (staining and FACS) and RNAi technique.

Results

Mitoxantrone, 5-Fu, adriamycin, Methotrexate, Pirarubicin, and Etoposide were identified as substrates of BCRP. However, Paclitaxel, Vincristine, Vindesine, Mitomycin C, and cisplatin were not mediated by BCRP. 5-Fu was identified as substrate of BCRP for the first time. The further study showed that the intracellular retention dose of 5-Fu and the 5-Fu induced cellular apoptosis all decreased when BCRP highly expressed. Furthermore, 5-Fu accumulation and 5-Fu induced DNA damage increased when BCRP was silenced by RNAi in breast cancer cells.

Conclusions

5-Fluorouracil may be a specific substrate which can be bound by BCRP. BCRP can predict the sensitivity of breast cancer to 5-Fu. And BCRP-targeted therapy will reverse the resistance of breast cancer to 5-Fu.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ABC:

ATP-binding cassette

BCRP:

Breast cancer resistance protein

5-Fu:

5-Fluorouracil

MDR:

Multidrug-resistant

MX:

Mitoxantrone

References

  1. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95(26):15665–15670

    Article  PubMed  CAS  Google Scholar 

  2. Schaub V, Hoffmann U, Blohmer JU, Grottke C, Mantwill K, Wichert A, Dietel M, Lage H (1997) Quantitative expression analysis of genes involved in development of chemoresistance in ovarian carcinoma in vitro and in vivo. 4th international symposium on cytostatic drug resistance, Berlin. Band of Abstracts, 96

  3. Ross DD, Karp JE, Chen TT, Doyle LA (2000) Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 96(1):365–368

    PubMed  CAS  Google Scholar 

  4. Bessho Y, Oguri T, Achiwa H, Muramatsu H, Maeda H, Niimi T, Sato S, Ueda R (2006) Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer. Cancer Sci 97(3):192–198

    Article  PubMed  CAS  Google Scholar 

  5. Kanzaki A, Toi M, Nakayama K, Bando H, Mutoh M, Uchida T, Fukumoto M, Takebayashi Y (2001) Expression of multidrug resistance-related transporters in human breast carcinoma. Jpn J Cancer Res 92(4):452–458

    PubMed  CAS  Google Scholar 

  6. Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau JH, Bates SE (2000) The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci 113(Pt 11):2011–2021

    PubMed  CAS  Google Scholar 

  7. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, Floot BG, Schellens JH (1999) Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59(18):4559–4563

    PubMed  CAS  Google Scholar 

  8. Nakanishi T, Karp JE, Tan M, Doyle LA, Peters T, Yang W, Wei D, Ross DD (2003) Quantitative analysis of breast cancer resistance protein and cellular resistance to flavopiridol in acute leukemia patients. Clin Cancer Res 9:3320–3328

    PubMed  CAS  Google Scholar 

  9. Lv H, He Z, Liu X, Yuan J, Yu Y, Chen Z (2007) Reversal of BCRP-mediated multidrug resistance by stable expression of small interfering RNAs. J Cell Biochem 102(1):75–81

    Article  PubMed  CAS  Google Scholar 

  10. Yuan JH, He ZM, Yu YH, Chen ZC (2004) Expression establishment and functional analysis of breast cancer resistance protein with doxycycline induced tet regulating system in mouse fibroblast cell line PA317. Ai Zheng 23(10):1127–1133

    PubMed  CAS  Google Scholar 

  11. Loos WJ, de Bruijn P, Verweij J, Sparreboom A (2000) Determination of camptothecin analogs in biological matrices by high-performance liquid chromatography. Anticancer Drugs 11(5):315–324

    Article  PubMed  CAS  Google Scholar 

  12. Kugawa F, Ueno A, Aoki M (2000) Apoptosis of NG108-15 cells induced by buprenorphine hydrochloride occurs via the caspase-3 pathway. Biol Pharm Bull 23(8):930–935

    PubMed  CAS  Google Scholar 

  13. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191

    Article  PubMed  CAS  Google Scholar 

  14. Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47(3):381–389

    Article  PubMed  CAS  Google Scholar 

  15. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258(5088):1650–1654

    Article  PubMed  CAS  Google Scholar 

  16. Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92(16):1295–1302

    Article  PubMed  CAS  Google Scholar 

  17. Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, Brangi M, Greenberger L, Dean M, Fojo T, Bates SE (1999) Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res 59(1):8–13

    PubMed  CAS  Google Scholar 

  18. Kugawa F, Ueno A, Kawasaki M, Aoki M (2004) Evaluation of cell death caused by CDF (cyclophosphamide, doxorubicin, 5-fluorouracil) multi-drug administration in the human breast cancer cell line MCF-7. Biol Pharm Bull 27(3):392–398

    Article  PubMed  CAS  Google Scholar 

  19. Oshaughnessy JA, Blum J, Moiseyenko V, Jones SE, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger HU, Laws S (2001) Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12(9):1247–1254

    Article  PubMed  CAS  Google Scholar 

  20. Rosa DD, Awada A, Cardoso F, Gil T, Lebrun F, Mano MS, Selleslags J, Piccart MJ, D’Hondt V (2007) Oxaliplatin and 5-fluorouracil in heavily pretreated patients with ovarian carcinoma: a well tolerated and efficient treatment. ASCO Meeting Abstracts, vol 25. p 16028

  21. Okamura M, Kobayashi M, Suzuki F, Shimada J, Sakagami H (2007) Induction of cell death by combination treatment with cisplatin and 5-fluorouracil in a human oral squamous cell carcinoma cell line. Anticancer Res 27(5A):3331–3337

    PubMed  CAS  Google Scholar 

  22. He Z, Yuan J, Chen Z, Liu S, Shen Z, Fei H (1998) Chemosensitivity test for 170 human breast carcinoma samples. Hunan Yi Ke Da Xue Xue Bao 23(6):531–534

    PubMed  CAS  Google Scholar 

  23. Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg AC, Schinkel AH, van De Vijver MJ, Scheper RJ, Schellens JH (2001) Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res 61(8):3458–3464

    PubMed  CAS  Google Scholar 

  24. Jonker JW, Smit JW, Brinkhuis RF, Maliepaard M, Beijnen JH, Schellens JH, Schinkel AH (2000) Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 92(20):1651–1656

    Article  PubMed  CAS  Google Scholar 

  25. Kruijtzer CM, Beijnen JH, Rosing H, ten Bokkel Huinink WW, Schot M, Jewell RC, Paul EM, Schellens JH (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol 20(13):2943–2950

    Article  PubMed  CAS  Google Scholar 

  26. Hoffmann U, Materna V, Blohmer JU (2000) Quantitative expression analysis of genes involved in the development of chemoresistance in ovarian carcinoma. Pathol Res Pract 196:235–238

    Google Scholar 

  27. Mao YS, Austin D, Ross DD (2001) BCRP gene expression in normal lung and in non-small cell lung cancer tissue. Chin J Cancer 20:274–278

    Google Scholar 

Download references

Acknowledgments

We thank Dr. Alfred H. Schinkel for kind gift of Ko143. Financial support: the Natural Science Foundation of Hunan Province, China (02JJY2052); the Basic Research Special Program of the Ministry of Science and Technology of China (2003CCC00700).

Author information

Authors and Affiliations

  1. Cancer Research Institute, Xiangya School of Medicine, Central South University, Xiangya Road #110, 410078, Changsha, Hunan, People’s Republic of China

    Jianhui Yuan, Hui Lv, Bo Peng, Chengkun Wang, Yanhui Yu & Zhimin He

Authors
  1. Jianhui Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bo Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chengkun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yanhui Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhimin He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhimin He.

Additional information

Jianhui Yuan and Hui Lv were contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yuan, J., Lv, H., Peng, B. et al. Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Cancer Chemother Pharmacol 63, 1103–1110 (2009). https://doi.org/10.1007/s00280-008-0838-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0838-z

Keywords

Search

Navigation