Assessment of Gene Expression Level of ATP Binding Cassette G Member 2 (ABCG2) Transporter in Newly Diagnosed Breast Cancer Patients Receiving Adjuvant Chemotherapy

• Shaimaa A. Soliman

  El-Salam Oncology Specialized Center, Ministry of Health, Cairo, Egypt

• Laila A. Rashed

  Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Egypt

• Mahmoud M. Said

  Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt

• Amina M. Medhat

  Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt

The efficacy of cancer chemotherapy is limited by cellular mechanisms of resistance that result in increased drug efflux of chemotherapeutic agents thereby reducing intracellular drug levels and causing drug resistance. Overexpression of some members of ATP binding cassette transporter superfamily, including ATP binding cassette G member 2 (ABCG2), which mediates energy-dependent transport of drugs out of the cells against concentration gradient, is one of the major mechanisms responsible for multidrug resistance in the treatment of breast cancer. In the current study, the expression of ABCG2 mRNA gene was evaluated in the peripheral blood of newly diagnosed breast cancer (NDBC) patients immediately before surgical resection of the breast and in extirpated breast tumors, then sequentially in the blood of patients after receiving three and six cycles of chemotherapy. Compared to normal breast, cancerous specimens expressed higher levels of ABCG2 gene expression (p<0.001). In addition, a gradual significant increase in the expression of peripheral blood ABCG2 gene of NDBC patients among different treatment periods was recorded. Furthermore, a significant positive correlation between peripheral blood ABCG2 gene expression of NDBC patients receiving chemotherapy and disease progression was found. In conclusion, assessment of ABCG2 gene expression may be a prerequisite in evaluating the effectiveness of chemotherapy-treated breast cancer patients.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA Cancer J Clin 2018; 68: 7-30. https://doi.org/10.3322/caac.21442

Globocan. Global Health Observatory 2018. http://gco.iarc.fr/today/data/factsheets/populations/818-egypt-fact-sheets.pdf

Gottesman MM, Lavi O, Hall MD, et al. Toward a Better Understanding of the Complexity of Cancer Drug Resistance. Annu Rev Pharmacol Toxicol 2016; 56: 85-102. https://doi.org/10.1146/annurev-pharmtox-010715-103111

Zahreddine H, Borden KL. Mechanisms and Insights into Drug Resistance in Cancer. Front Pharmacol 2013; 4: 28. https://doi.org/10.3389/fphar.2013.00028

Khunweeraphong N, Szöllősi D, Stockner D. et al. The ABCG2 Multidrug Transporter is a Pump Gated by a Valve and an Extracellular Lid. Nat Commun 2019; 10(1): 5433. https://doi.org/10.1038/s41467-019-13302-2

Bhardwaj B, Baidya ATK, Amin SA, et al. Insight into Structural Features of Phenyltetrazole Derivatives as ABCG2 Inhibitors for the Treatment of Multidrug Resistance in Cancer. SAR QSAR Environ Res 2019; 30: 457-475. https://doi.org/10.1080/1062936X.2019.1615545

Toyoda Y, Takada T, Suzuki H. Inhibitors of Human ABCG2: From Technical Background to Recent Updates with Clinical Implications. Front Pharmacol 2019; 10: 208. https://doi.org/10.3389/fphar.2019.00208

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 2009; 63(6): 1103-10. https://doi.org/10.1007/s00280-008-0838-z

Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2(-Delta Delta C (T)) Method. Methods 2001; 25: 402-408. https://doi.org/10.1006/meth.2001.1262

Liu L, Zuo LF, Guo JW. ABCG2 Gene Amplification and Expression in Esophageal Cancer Cells with Acquired Adriamycin Resistance. Mol Med Rep 2014; 9: 1299-1304. https://doi.org/10.3892/mmr.2014.1949

Kalimutho M, Parsons K, Mittal D, et al. Targeted therapies for triple-negative breast cancer: Combating a stubborn disease. Trends Pharmacol Sci 2015; 36: 822-846. https://doi.org/10.1016/j.tips.2015.08.009

Bartholomae S, Gruhn B, Debatin KM, et al. Co-expression of Multiple ABC-Transporters is Strongly Associated with Treatment Response in Childhood Acute Myeloid Leukemia. Pediatr Blood Cancer 2016; 63: 242-247. https://doi.org/10.1002/pbc.25785

Omran OM. The prognostic Value of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression in Breast Carcinomas. J Environ Pathol Toxicol Oncol 2012; 31: 367-376. https://doi.org/10.1615/JEnvironPatholToxicolOncol.2013006767

Collina F, Di Bonito M, Li Bergolis V, et al. Prognostic Value of Cancer Stem Cells Markers in Triple-Negative Breast Cancer. BioMed Res Int 2015. https://doi.org/10.1155/2015/158682

Zhang W, Yu F, Wang Y, et al. Rab23 Promotes the Cisplatin Resistance of Ovarian Cancer via the Shh-Gli-ABCG2 Signaling Pathway. Oncol Lett 2018; 15: 5155-5160. https://doi.org/10.3892/ol.2018.7949

Palasuberniam P, Yang X, Kraus D, et al. ABCG2 Transporter Inhibitor Restores the Sensitivity of Triple Negative Breast Cancer Cells to Aminolevulinic Acid-Mediated Photodynamic Therapy. Sci Rep 2015; 5. https://doi.org/10.1038/srep13298

Gerk PM, Vore M. Regulation of Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) and its Role in Drug Disposition. J Pharmacol Exp Ther 2002; 302: 407-415. https://doi.org/10.1124/jpet.102.035014

Chen YL, Chen PM, Lin PY, et al. ABCG2 overexpression confers poor outcomes in hepatocellular carcinoma of elderly patients. Anticancer Res 2016; 36: 2983-2988.

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