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Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer

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Abstract

Background

ATP-binding cassette (ABC) transporters are responsible for the efflux of a wide variety of anti-cancer agents and have been implicated in the chemoresistance of various solid tumors. Chemoresistance is a major cause of therapeutic failure, especially in the highly aggressive triple-negative breast cancer (TNBC) in which, unlike estrogen receptor-expressing (ER+) BC, both endocrine and targeted treatments are ineffectual. We aimed to investigate the level and frequency of expression of the three most important ABC transporter, ABCG2, ABCC1, and ABCB1, according to breast cancer subtype.

Methods

We evaluated ABCG2, ABCC1, and ABCB1 protein expressions in 124 primary breast tumors (78 samples were classified as TNBC, while 46 were classified as ER+) by immunohistochemistry and correlated it to clinicopathological characteristics and outcome.

Results

All three transporters had significantly higher expression and were more frequently expressed in TNBC compared to ER+ tumors (p < 0.0001). ABCG2 and ABCC1 had a very high level of expression in TNBC that was significantly greater compared to ABCB1 (p < 0.0001). ABCB1 expression was associated with TNBC metastatic spread (p = 0.03). In contrast, TNBC patients with high ABCG2 expression level had significantly longer disease-free interval (p = 0.03) and overall survival (p = 0.007).

Conclusion

ABCG2, ABCC1, and ABCB1 expression in breast cancer is subtype-specific and associated with triple-negative tumors. The expression of ABCB1 may be useful as a marker of metastatic spread. Moreover, unexpectedly, our results showed a beneficial effect of ABCG2 expression on TNBC clinical behavior. These findings could have implications for the implementation of future TNBC treatment strategies.

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References

  1. Turashvili G, Brogi E. Tumor heterogeneity in breast cancer. Front Med. 2017;2017:4.

    Google Scholar 

  2. Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American society of clinical oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.

    Article  CAS  Google Scholar 

  3. Lebert JM, Lester R, Powell E, Seal M, McCarthy J. Advances in the systemic treatment of triple-negative breast cancer. Curr Oncol. 2018;25:S142–50.

    Article  CAS  Google Scholar 

  4. Nedeljković M, Damjanović A. Mechanisms of chemotherapy resistance in triple-negative breast cancer—how we can rise to the challenge. Cells. 2019;8:957.

    Article  Google Scholar 

  5. Longley D, Johnston P. Molecular mechanisms of drug resistance. J Pathol. 2005;205:275–92.

    Article  CAS  Google Scholar 

  6. Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding Cassette (ABC) Transporter Family. Hum Genomics. 2009;3:281–90.

    Article  CAS  Google Scholar 

  7. Wu C-P, Calcagno A, Ambudkar S. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol. 2008;1:93–105.

    Article  CAS  Google Scholar 

  8. Sharom FJ. ABC multi-drug transporters: structure, function and role in chemoresistance. Pharmacogenomics. 2008;9:105–27.

    Article  CAS  Google Scholar 

  9. He S-M, Li R, Kanwar RJ, Zhou S-F. Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1). Curr Med Chem. 2011;18:439–81.

    Article  CAS  Google Scholar 

  10. Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14:3–9.

    Article  Google Scholar 

  11. Choi Y, Yu A-M. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr Pharm Des. 2014;20:793–807.

    Article  CAS  Google Scholar 

  12. Leake R. Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. J Clin Pathol. 2000;53:634–5.

    Article  CAS  Google Scholar 

  13. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of clinical oncology/college of american pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36:2105–22.

    Article  CAS  Google Scholar 

  14. Ibis K, Ozkurt S, Kucucuk S, Yavuz E, Saip P. Comparison of pathological prognostic stage and anatomic stage groups according to the Updated Version of the American Joint Committee on Cancer (AJCC) Breast Cancer Staging 8th Edition. Med Sci Monit. 2018;24:3637–43.

  15. Ding XW, Wu JH, Jiang CP. ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci Elsevier Inc 2010;86:631–7.

  16. Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD. Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol. 2010;44:152–67.

    Article  CAS  Google Scholar 

  17. Leonessa F, Clarke R. ATP binding cassette transporters and drug resistance in breast cancer. Endocr Relat Cancer. 2003;10:43–73.

    Article  CAS  Google Scholar 

  18. Yamada A, Ishikawa T, Ota I, Kimura M, Shimizu D, Tanabe M, et al. 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. 2013;137:773–82.

    Article  CAS  Google Scholar 

  19. Xiang L, Su P, Xia S, Liu Z, Wang Y, Gao P, et al. ABCG2 is associated with HER-2 expression, lymph node metastasis and clinical stage in breast invasive ductal carcinoma. Diagn Pathol. 2011;6:90.

    Article  Google Scholar 

  20. Dexter DW, Reddy RK, Geles KG, Bansal S, Myint MA, Rogakto A, Leighton JC, Goldstein LJ. Quantitative reverse transcriptase-polymerase chain reaction measured expression of MDR1 and MRP in primary breast carcinoma. Clin Cancer Res. 1998;4:1533–42.

    CAS  PubMed  Google Scholar 

  21. Faneyte IF, Kristel PMP, van de Vijver MJ. Determining MDR1/P-glycoprotein expression in breast cancer. Int J Cancer. 2001;93:114–22.

    Article  CAS  Google Scholar 

  22. Ruban EL, Ferro R, Arifin SA, Falasca M. Lysophosphatidylinositol: a novel link between ABC transporters and G-protein-coupled receptors. Biochem Soc Trans. 2014;42:1372–7.

    Article  CAS  Google Scholar 

  23. Domenichini A, Adamska A, Falasca M. ABC transporters as cancer drivers: potential functions in cancer development. Biochim Biophys Acta Gen Subj. 2019;1863:52–60.

    Article  CAS  Google Scholar 

  24. Kuss BJ, Corbo M, Lau WM, Fennell DA, Dean NM, Cotter FE. In vitro and in vivo downregulation of MRP1 by antisense oligonucleotides: a potential role in neuroblastoma therapy. Int J Cancer. 2002;98:128–33.

    Article  CAS  Google Scholar 

  25. Imai Y, Ishikawa E, Asada S, Sugimoto Y. Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2. Cancer Res. 2005;65:596–605.

    Article  CAS  Google Scholar 

  26. Wu X, Zhang X, Zhang H, Su P, Li W, Li L, et al. Progesterone receptor downregulates breast cancer resistance protein expression via binding to the progesterone response element in breast cancer. Cancer Sci. 2012;103:959–67.

    Article  CAS  Google Scholar 

  27. Mutoh K, Tsukahara S, Mitsuhashi J, Katayama K, Sugimoto Y. Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells. Cancer Sci. 2006;97:1198–204.

    Article  CAS  Google Scholar 

  28. Rudas M, Filipits M, Taucher S, Stranzl T, Steger GG, Jakesz R, et al. Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. Breast Cancer Res Treat. 2003;81:149–57.

    Article  CAS  Google Scholar 

  29. Kanzaki A, Toi M, Nakayama K, Bando H, Mutoh M, Uchida T, et al. Expression of multi-drug resistance-related transporters in human breast carcinoma. Jpn J Cancer Res. 2001;92:452–8.

    Article  CAS  Google Scholar 

  30. Moureau-Zabotto L, Ricci S, Lefranc JP, Coulet F, Genestie C, Antoine M, et al. Prognostic impact of multi-drug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patients. Br J Cancer. 2006;94:473–80.

    Article  CAS  Google Scholar 

  31. Omran OM. The prognostic value of breast cancer resistance protein (BCRP/ABCG2) expression in breast carcinomas. J Environ Pathol Toxicol Oncol. 2012;31:367–76.

    Article  Google Scholar 

  32. Kim B, Fatayer H, Hanby AM, Horgan K, Perry SL, Valleley EMA, et al. Neoadjuvant chemotherapy induces expression levels of breast cancer resistance protein that predict disease-free survival in breast cancer. PLoS ONE. 2013;8:1–8.

    Article  CAS  Google Scholar 

  33. Lu LS, Chen L, Ding WX, Li K, Wu JJ. Elevated expression of both MDR1 and MMP-2 genes in metastasized lymph node of invasive ductal breast cancer. Eur Rev Med Pharmacol Sci. 2012;16:2037–43.

    CAS  PubMed  Google Scholar 

  34. Surowiak P, Materna V, Matkowski R, Szczuraszek K, Kornafel J, Wojnar A, et al. Relationship between the expression of cyclooxygenase 2 and MDR1/P-glycoprotein in invasive breast cancers and their prognostic significance. Breast Cancer Res. 2005;7:R862–70.

    Article  CAS  Google Scholar 

  35. Larbcharoensub N, Sornmayura P, Sirachainan E, Wilasrusmee C, Wanmoung H, Janvilisri T. Prognostic value of ABCG2 in moderately and poorly differentiated intrahepatic cholangiocarcinoma. Histopathology. 2011;59:235–46.

    Article  Google Scholar 

  36. Namisaki T, Schaeffeler E, Fukui H, Yoshiji H, Nakajima Y, Fritz P, et al. Differential expression of drug uptake and efflux transporters in japanese patients with hepatocellular carcinoma. Drug Metab Dispos. 2014;42:2033–40.

    Article  Google Scholar 

  37. O'Conor CJ, Chen T, González I, Cao D, Peng Y. Cancer stem cells in triple-negative breast cancer: a potential target and prognostic marker. Biomark Med. 2018;12:813–20.

    Article  CAS  Google Scholar 

  38. Nie S, Huang Y, Shi M, Qian X, Li H, Peng C, et al. Protective role of ABCG2 against oxidative stress in colorectal cancer and its potential underlying mechanism. Oncol Rep. 2018;40:2137–46.

    CAS  PubMed  Google Scholar 

  39. Liao Z, Chua D, Tan NS. Reactive oxygen species: a volatile driver of field cancerization and metastasis. Mol Cancer Molecular Cancer. 2019;18:1–10.

    Article  CAS  Google Scholar 

  40. Liang SC, Yang CY, Tseng JY, Wang HL, Tung CT, Liu HW, et al. ABCG2 localizes to the nucleus and modulates CDH1 expression in lung cancer cells. Neoplasia. 2015;17(3):265–78.

    Article  CAS  Google Scholar 

  41. Neophytou C, Boutsikos P, Papageorgis P. Molecular mechanisms and emerging therapeutic targets of triple-negative breast cancer metastasis. Front Oncol. 2018;2018:8.

    Google Scholar 

Download references

Funding

This research was funded by the Ministry of Education, Science and Technological Development, Republic of Serbia, Grant nos. III41031 and ON173049.

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Authors and Affiliations

  1. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia

    Milica Nedeljković

  2. Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, National Institute of Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11351, Belgrade, Serbia

    Nasta Tanić

  3. Institute of Pathology, Faculty of Medicine, University of Belgrade, Doktora Subotića 1, 11000, Belgrade, Serbia

    Mirjana Prvanović

  4. Department for Pathology and Cytology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia

    Zorka Milovanović

  5. Department of Neurobiology, Institute for Biological Research “Siniša Stanković”-National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11000, Belgrade, Serbia

    Nikola Tanić

Authors
  1. Milica Nedeljković
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  2. Nasta Tanić
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Correspondence to Milica Nedeljković.

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Conflict of interest

All authors report grants from the Ministry of Education, Science and Technological Development, Republic of Serbia, during the conduct of the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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The retrospective study was approved by the Ethics Committee of the Institute for oncology and radiology of Serbia, number 4321-01. For this type of study, formal consent is not required.

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Nedeljković, M., Tanić, N., Prvanović, M. et al. Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer. Breast Cancer 28, 727–736 (2021). https://doi.org/10.1007/s12282-020-01210-z

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  • DOI: https://doi.org/10.1007/s12282-020-01210-z

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