Advertisement

Journal of Genetics

, Volume 97, Issue 5, pp 1185–1194 | Cite as

Single-nucleotide polymorphisms and mRNA expression of CYP1B1 influence treatment response in triple negative breast cancer patients undergoing chemotherapy

  • Ahmad Aizat Abdul aziz
  • MD Salzihan MD Salleh
  • Ibtisam Mohamad
  • Venkata Murali Krishna Bhavaraju
  • Maya Mazuwin Yahya
  • Andee Dzulkarnaen Zakaria
  • Siew Hua Gan
  • Ravindran AnkathilEmail author
Research Article
  • 59 Downloads

Abstract

Triple negative breast cancer (TNBC) is typically associated with poor and interindividual variability in treatment response. Cytochrome P450 family 1 subfamily B1 (CYP1B1) is a metabolizing enzyme, involved in the biotransformation of xenobiotics and anticancer drugs. We hypothesized that, single-nucleotide polymorphisms (SNPs), CYP1B1 142 \(\hbox {C}{>}\hbox {G}\), 4326 \(\hbox {C}{>}\hbox {G}\) and 4360 \(\hbox {A}{>}\hbox {G}\), and CYP1B1 mRNA expression might be potential biomarkers for prediction of treatment response in TNBC patients. CYP1B1 SNPs genotyping (76 TNBC patients) was performed using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods and mRNA expression of CYP1B1 (41 formalin-fixed paraffin embedded blocks) was quantified using quantitative reverse transcription PCR. Homozygous variant genotype (GG) and variant allele (G) of CYP1B1 4326 \(\hbox {C}{>}\hbox {G}\) polymorphism showed significantly higher risk for development of resistance to chemotherapy with adjusted odds ratio (OR): 6.802 and 3.010, respectively. Whereas, CYP1B1 142 CG heterozygous genotype showed significant association with good treatment response with adjusted OR: 0.199. CYP1B1 142C-4326G haplotype was associated with higher risk for chemoresistance with OR: 2.579. Expression analysis revealed that the relative expression of CYP1B1 was downregulated (0.592) in cancerous tissue compared with normal adjacent tissues. When analysed for association with chemotherapy response, CYP1B1 expression was found to be significantly upregulated (3.256) in cancerous tissues of patients who did not respond as opposed to those of patients who showed response to chemotherapy. Our findings suggest that SNPs together with mRNA expression of CYP1B1 may be useful biomarkers to predict chemotherapy response in TNBC patients.

Keywords

triple negative breast cancer cytochrome P450 family 1 subfamily B1 single-nucleotide polymorphisms mRNA chemotherapy response 

Notes

Acknowledgements

This study was supported by Universiti Sains Malaysia, Research University Team (RUT) Grant (1001/PPSP/853005).

References

  1. Barrett J. C., Fry B., Maller J. and Daly M. J. 2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265.CrossRefGoogle Scholar
  2. Boyle P. 2012 Triple-negative breast cancer: epidemiological considerations and recommendations. Ann. Oncol. 23, suppl. 6, vi7–12.Google Scholar
  3. Buyukhatipoglu H., Babacan T., Kertmen N., Balakan O., Suner A., Ates O. et al. 2015 A retrospective analysis of adjuvant CAF, AC-T and TAC regimens in triple negative early stage breast cancer. J. BUON 20, 22–27.PubMedGoogle Scholar
  4. Cavalieri F. 1996 Drugs that target gene expression: an overview. Crit. Rev. Eukaryotic Gene Expression 6, 75–85.CrossRefGoogle Scholar
  5. Chang I., Mitsui Y., Fukuhara S., Gill A., Wong D. K., Yamamura S. et al. 2015 Loss of miR-200c up-regulates CYP1B1 and confers docetaxel resistance in renal cell carcinoma. Oncotarget 6, 7774–7787.PubMedPubMedCentralGoogle Scholar
  6. Chun Y. J. and Kim S. 2003 Discovery of cytochrome P450 1B1 inhibitors as new promising anti-cancer agents. Med. Res. Rev. 23, 657–668.CrossRefGoogle Scholar
  7. Dogra A., Doval D. C., Sardana M., Chedi S. K. and Mehta A. 2014 Clinicopathological characteristics of triple negative breast cancer at a tertiary care hospital in India. Asian Pac. J. Cancer Prev. 15, 10577–10583.CrossRefGoogle Scholar
  8. Dumont A., Pannier D., Ducoulombier A., Tresch E., Chen J., Kramar A. et al. 2015 ERCC1 and CYP1B1 polymorphisms as predictors of response to neoadjuvant chemotherapy in estrogen positive breast tumors. SpringerPlus 4, 327.CrossRefGoogle Scholar
  9. Evans B. R., Karchner S. I., Allan L. L., Pollenz R. S., Tanguay R. L. and Jenny M. J. 2008 Repression of aryl hydrocarbon receptor (AHR) signaling by AHR repressor: role of DNA binding and competition for AHR nuclear translocator. Mol. Pharmacol. 73, 387–398.CrossRefGoogle Scholar
  10. Foulkes W. D., Smith I. E. and Reis-Filho J. S. 2010 Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948.CrossRefGoogle Scholar
  11. Gajjar K., Martin-Hirsch P. L. and Martin F. L. 2012 CYP1B1 and hormone-induced cancer. Cancer Lett. 324, 13–30.CrossRefGoogle Scholar
  12. Gehrmann M., Schmidt M., Brase J. C., Roos P. and Hengstler J. G. 2008 Prediction of paclitaxel resistance in breast cancer: is CYP1B1*3 a new factor of influence? Pharmacogenomics 9, 969–974.CrossRefGoogle Scholar
  13. Goldhirsch A., Wood W. C., Coates A. S., Gelber R. D., Thurlimann B., Senn H. J. et al. 2011 Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann. Oncol. 22, 1736–1747.CrossRefGoogle Scholar
  14. Goldman B. 2003 Multidrug resistance: can new drugs help chemotherapy score against cancer? J. Natl. Cancer Inst. 95, 255–257.CrossRefGoogle Scholar
  15. Gribben J. G., Ryan D. P., Boyajian R., Urban R. G., Hedley M. L., Beach K. et al. 2005 Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy. Clin. Cancer Res. 11, 4430–4436.CrossRefGoogle Scholar
  16. Haarmann-Stemmann T., Bothe H., Kohli A., Sydlik U., Abel J. and Fritsche E. 2007 Analysis of the transcriptional regulation and molecular function of the aryl hydrocarbon receptor repressor in human cell lines. Drug Metab. Dispos. 35, 2262–2269.CrossRefGoogle Scholar
  17. Hammond M E., Hayes D F., Dowsett M, Allred D. C., Hagerty K. L. and Badve S. 2010 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J. Clin. Oncol. 28, 2784–2795.CrossRefGoogle Scholar
  18. Hanna I. H., Dawling S., Roodi N., Guengerich F. P. and Parl F. F. 2000 Cytochrome P450 1B1 (CYP1B1) pharmacogenetics: association of polymorphisms with functional differences in estrogen hydroxylation activity. Cancer Res. 60, 3440–3444.PubMedGoogle Scholar
  19. Hevir N., Sinkovec J. and Rizner T. L. 2011 Disturbed expression of phase I and phase II estrogen-metabolizing enzymes in endometrial cancer: lower levels of CYP1B1 and increased expression of S-COMT. Mol. Cell Endocrinol. 331, 158–167.CrossRefGoogle Scholar
  20. Housman G., Byler S., Heerboth S., Lapinska K., Longacre M., Snyder N. et al. 2014 Drug resistance in cancer: an overview. Cancers (Basel). 6, 1769–1792.CrossRefGoogle Scholar
  21. Landi M. T., Bergen A. W., Baccarelli A., Patterson D. G. Jr., Grassman J., Ter-Minassian M. et al. 2005 CYP1A1 and CYP1B1 genotypes, haplotypes, and TCDD-induced gene expression in subjects from Seveso, Italy. Toxicology 207, 191–202.CrossRefGoogle Scholar
  22. Laroche-Clary A., Le Morvan V., Yamori T. and Robert J. 2010 Cytochrome P450 1B1 gene polymorphisms as predictors of anticancer drug activity: studies with in vitro models. Mol. Cancer Ther. 9, 3315–3321.CrossRefGoogle Scholar
  23. Lepine J., Audet-Walsh E., Gregoire J., Tetu B., Plante M., Menard V. et al. 2010 Circulating estrogens in endometrial cancer cases and their relationship with tissular expression of key estrogen biosynthesis and metabolic pathways. J. Clin. Endocrinol. Metab. 95, 2689–2698.CrossRefGoogle Scholar
  24. Liedtke C., Mazouni C., Hess K. R., Andre F., Tordai A., Mejia J. A. et al. 2008 Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 26, 1275–1281.CrossRefGoogle Scholar
  25. Marsh S., Somlo G., Li X., Frankel P., King C. R., Shannon W. D. et al. 2007 Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. Pharmacogenomics J. 7, 362–365.CrossRefGoogle Scholar
  26. Martinez V. G., O’Connor R., Liang Y. and Clynes M. 2008 CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. Br. J. Cancer 98, 564–570.CrossRefGoogle Scholar
  27. McFadyen M. C., McLeod H. L., Jackson F. C., Melvin W. T., Doehmer J. and Murray G. I. 2001 Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. Biochem. Pharmacol. 62, 207–212.CrossRefGoogle Scholar
  28. McLellan R. A., Oscarson M., Hidestrand M., Leidvik B., Jonsson E., Otter C. et al. 2000 Characterization and functional analysis of two common human cytochrome P450 1B1 variants. Arch. Biochem. Biophys. 378, 175–181.CrossRefGoogle Scholar
  29. Michael M. and Doherty M. M. 2005 Tumoral drug metabolism: overview and its implications for cancer therapy. J. Clin. Oncol. 23, 205–229.CrossRefGoogle Scholar
  30. Modugno F., Knoll C., Kanbour-Shakir A. and Romkes M. 2003 A potential role for the estrogen-metabolizing cytochrome P450 enzymes in human breast carcinogenesis. Breast Cancer Res. Treat. 82, 191–197.CrossRefGoogle Scholar
  31. Muthusamy V., Duraisamy S., Bradbury C. M., Hobbs C., Curley D. P., Nelson B. et al. 2006 Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 66, 11187–11193.CrossRefGoogle Scholar
  32. Pastina I., Giovannetti E., Chioni A., Sissung T. M., Crea F., Orlandini C. et al. 2010 Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients. BMC Cancer 10, 511.CrossRefGoogle Scholar
  33. Pfaffl M. W., Horgan G. W. and Dempfle L. 2002 Relative expression software tool (REST (c)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30, e36.CrossRefGoogle Scholar
  34. Pogoda K., Niwinska A., Murawska M. and Pienkowski T. 2013 Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med. Oncol. 30, 388.CrossRefGoogle Scholar
  35. Pradhan S., Nagashri M. N., Gopinath K. S. and Kumar A. 2011 Expression profiling of CYP1B1 in oral squamous cell carcinoma: counterintuitive downregulation in tumors. PLoS One 6, e27914.CrossRefGoogle Scholar
  36. Qiu J. D., Xue X. Y., Li R. and Wang J. D. 2016 Clinicopathological features and prognosis of triple-negative breast cancer: a comparison between younger (\(<60\)) and elderly (\({\ge }60\)) patients. Eur. J. Cancer Care 25, 1065–1075.CrossRefGoogle Scholar
  37. Rizzo R., Spaggiari F., Indelli M., Lelli G., Baricordi O. R., Rimessi P. et al. 2010 Association of CYP1B1 with hypersensitivity induced by Taxane therapy in breast cancer patients. Breast Cancer Res. Treat. 124, 593–598.CrossRefGoogle Scholar
  38. Rochat B. 2005 Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance – focus on tamoxifen, paclitaxel and imatinib metabolism. Clin. Pharmacokinet. 44, 349–366.CrossRefGoogle Scholar
  39. Shimada T., Watanabe J., Kawajiri K., Sutter T. R., Guengerich F. P., Gillam E. M. J. et al. 1999 Catalytic properties of polymorphic human cytochrome P4501B1 variants. Carcinogenesis 20, 1607–1613.CrossRefGoogle Scholar
  40. Singh M. N., Stringfellow H. F., Walsh M. J., Ashton K. M., Paraskevaidis E., Abdo K. R. et al. 2008 Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium. Toxicology 249, 85–90.CrossRefGoogle Scholar
  41. Sissung T. M., Danesi R., Price D. K., Steinberg S. M., de Wit R., Zahid M. et al. 2008 Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. Mol. Cancer Ther. 7, 19–26.CrossRefGoogle Scholar
  42. Takemura H., Itoh T., Yamamoto K., Sakakibara H. and Shimoi K. 2010 Selective inhibition of methoxyflavonoids on human CYP1B1 activity. Bioorg. Med. Chem. 18, 6310–6315.CrossRefGoogle Scholar
  43. Tecza K., Pamula-Pilat J., Lanuszewska J. and Grzybowska E. 2016 Genetic polymorphisms and response to 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients. Oncotarget 7, 66790–66808.CrossRefGoogle Scholar
  44. Trubicka J., Grabowska-Klujszo E., Suchy J., Masojc B., Serrano-Fernandez P., Kurzawski G. et al. 2010 Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility. BMC Cancer 10, 420.CrossRefGoogle Scholar
  45. Tsuchiya Y., Nakajima M. and Yokoi, T. 2005 Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 227, 115–124.CrossRefGoogle Scholar
  46. Tsuchiya Y., Nakajima M., Takagi S., Taniya T. and Yokoi T. 2006 MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res. 66, 9090–9098.CrossRefGoogle Scholar
  47. Tulsyan S., Chaturvedi P., Singh A. K., Agarwal G., Lal P., Agrawal S. et al. 2014 Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach. Gene 543, 69–75.CrossRefGoogle Scholar
  48. Vaclavikova R., Hubackova M., Stribrna-Sarmanova J., Kodet R., Mrhalova M., Novotny J. et al. 2007 RNA expression of cytochrome P450 in breast cancer patients. Anticancer Res. 27, 4443–4450.PubMedGoogle Scholar
  49. van Roozendaal L. M., Smit L. H. M., Duijsens G., de Vries B., Siesling S., Lobbes M. B. I. et al. 2016 Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study. Breast Cancer Res. Treat. 156, 465–472.CrossRefGoogle Scholar
  50. Yager J. D. 2012 Catechol-O-methyltransferase: characteristics, polymorphisms and role in breast cancer. Drug Discov. Today Dis. Mech. 9, e41–e46.CrossRefGoogle Scholar
  51. Zhu Z., Mu Y., Qi C., Wang J., Xi G., Guo J. et al. 2015 CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro. Int. J. Mol. Med. 35, 340–348.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  • Ahmad Aizat Abdul aziz
    • 1
  • MD Salzihan MD Salleh
    • 2
  • Ibtisam Mohamad
    • 3
  • Venkata Murali Krishna Bhavaraju
    • 4
  • Maya Mazuwin Yahya
    • 5
  • Andee Dzulkarnaen Zakaria
    • 5
  • Siew Hua Gan
    • 6
  • Ravindran Ankathil
    • 1
    Email author
  1. 1.Human Genome CentreUniversiti Sains MalaysiaKubang KerianMalaysia
  2. 2.Department of Pathology, School of Medical SciencesUniversiti Sains MalaysiaKubang KerianMalaysia
  3. 3.Department of PathologyHospital Raja Perempuan Zainab IIKota BharuMalaysia
  4. 4.Adventist Oncology CenterPenang Adventist HospitalPulau PinangMalaysia
  5. 5.Department of Surgery, School of Medical SciencesUniversiti Sains MalaysiaKubang KerianMalaysia
  6. 6.PharmacyMonash University MalaysiaBandar SunwayMalaysia

Personalised recommendations