Skip to main content

Advertisement

Log in

Doxorubicin–paclitaxel sequential treatment: insights of DNA methylation and gene expression changes of luminal A and triple negative breast cancer cell lines

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Breast cancer is one of the significant causes of death among women diagnosed with cancer worldwide. Even though several chemotherapy combinations are still the primary treatment of breast cancer, unsuccessful treatments, and poor prognostic outcomes are still being reported. DNA methylation and gene expression changes among two breast cancer cell lines representing luminal A (MCF-7) and triple-negative (MDA-MB-231) cancers were determined after sequential combination treatment of doxorubicin and paclitaxel and analyzed using Ingenuity Pathway Analysis. Promoter methylation changes were seen in different treated MCF-7 cells and accompanied by changes in the gene expression of CCNA1 and PTGS2. In MDA-MB-231 cells, the hypomethylation of ESR1 was not accompanied by an increase in its gene expression in any treated cells. The hypomethylation of GSTP1 and MGMT was accompanied by an increase in gene expression levels in the group treated with doxorubicin only. Also, significant downregulation of several genes like MUC1 and MKI67 in MCF-7 cells treated with doxorubicin showed much lower gene expression (− 37.63, − 10.88 folds) when compared with cells treated with paclitaxel (− 2.47, − 2.05 folds) or the combination treatment (− 18.99, − 2.81 folds), respectively. On the other hand, a synergistic effect on MMP9 gene expression was significantly seen in MDA-MB-231 cells treated with the combination (− 9.99 folds) in comparison with the cells treated with doxorubicin (− 3.62 folds) or paclitaxel (1.75 folds) alone. Chemotherapy combinations do not always augment the molecular changes seen in each drug alone, and these changes could be utilized as treatment response markers.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144(8):1941–1953

    Article  CAS  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  3. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, Jemal A, Siegel RL (2019) Breast cancer statistics, 2019. CA Cancer J Clin 69(6):438–451

    Article  Google Scholar 

  4. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S, Senkus E (2019) Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 30(8):1194–1220

    Article  CAS  Google Scholar 

  5. Park YH, Senkus-Konefka E, Im SA, Pentheroudakis G, Saji S, Gupta S, Iwata H, Mastura MY, Dent R, Lu YS, Yin Y (2020) Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS. Ann Oncol 31(4):451–469

    Article  CAS  Google Scholar 

  6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Peto R, Davies C, Godwin J, et al (2012) Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. The Lancet 379(9814):432–444. https://doi.org/10.1016/S0140-6736(11)61625-5

  7. Giordano SH, Temin S, Chandarlapaty S, Crews JR, Esteva FJ, Kirshner JJ, Krop IE, Levinson J, Lin NU, Modi S, Patt DA (2018) Systemic therapy for patients with advanced human epidermal growth factor receptor 2–positive breast cancer: ASCO clinical practice guideline update. J Clin Oncol 36(26):2736–2740

    Article  Google Scholar 

  8. Chen ST, Pan TL, Tsai YC, Huang CM (2002) Proteomics reveals protein profile changes in doxorubicin–treated MCF-7 human breast cancer cells. Cancer Lett 181(1):95–107

    Article  CAS  Google Scholar 

  9. Yu J, Wang Y, Zhou S, Li J, Wang J, Chi D, Wang X, Lin G, He Z, Wang Y (2020) Remote loading paclitaxel–doxorubicin prodrug into liposomes for cancer combination therapy. Acta Pharm Sin B. https://doi.org/10.1016/j.apsb.2020.04.011

    Article  PubMed  PubMed Central  Google Scholar 

  10. Alqahtani FY, Aleanizy FS, El Tahir E, Alkahtani HM, AlQuadeib BT (2019) Paclitaxel. Profiles of drug substances, excipients and related methodology, vol 44. Academic Press, Cambridge, pp 205–238

    Google Scholar 

  11. Shim G, Kim MG, Kim D, Park JY, Oh YK (2017) Nanoformulation-based sequential combination cancer therapy. Adv Drug Deliv Rev 115:57–81

    Article  CAS  Google Scholar 

  12. Ntellas P, Spathas N, Agelaki S, Zintzaras E, Saloustros E (2019) Taxane & cyclophosphamide vs anthracycline & taxane-based chemotherapy as adjuvant treatment for breast cancer: a pooled analysis of randomized controlled trials by the Hellenic Academy of Oncology. Oncotarget 10(11):1209

    Article  Google Scholar 

  13. Chaudhary LN (2020) Early stage triple negative breast cancer: management and future directions. Semin Oncol. https://doi.org/10.1053/j.seminoncol.2020.05.006

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dejeux E, Rønneberg JA, Solvang H, Bukholm I, Geisler S, Aas T, Gut IG, Børresen-Dale AL, Lønning PE, Kristensen VN, Tost J (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol Cancer 9(1):68

    Article  Google Scholar 

  15. Kastl L, Brown I, Schofield AC (2010) Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int J Oncol 36(5):1235–1241

    CAS  PubMed  Google Scholar 

  16. de Ruijter TC, van der Heide F, Smits KM, Aarts MJ, van Engeland M, Heijnen VC (2020) Prognostic DNA methylation markers for hormone receptor breast cancer: a systematic review. Breast Cancer Res 22(1):1–2

    Article  Google Scholar 

  17. Shakeri H, Gharesouran J, Fakhrjou A, Esfahani A, Ardebili SM (2016) DNA methylation assessment as a prognostic factor in invasive breast cancer using methylation-specific multiplex ligation dependent probe amplification. EXCLI J 15:11

    PubMed  PubMed Central  Google Scholar 

  18. Klajic J, Fleischer T, Dejeux E, Edvardsen H, Warnberg F, Bukholm I, Lønning PE, Solvang H, Børresen-Dale AL, Tost J, Kristensen VN (2013) Quantitative DNA methylation analyses reveal stage dependent DNA methylation and association to clinico-pathological factors in breast tumors. BMC Cancer 13(1):456

    Article  Google Scholar 

  19. An N, Shi Y, Ye P, Pan Z, Long X (2017) Association between MGMT promoter methylation and breast cancer: a meta-analysis. Cell Physiol Biochem 42(6):2430–2440

    Article  CAS  Google Scholar 

  20. Temian DC, Pop LA, Irimie AI, Berindan-Neagoe I (2018) The epigenetics of triple-negative and basal-like breast cancer: current knowledge. J Breast Cancer 21(3):233–243

    Article  Google Scholar 

  21. García-Quiroz J, Rivas-Suárez M, García-Becerra R, Barrera D, Martínez-Reza I, Ordaz-Rosado D, Santos-Martinez N, Villanueva O, Santos-Cuevas CL, Avila E, Gamboa-Domínguez A (2014) Calcitriol reduces thrombospondin-1 and increases vascular endothelial growth factor in breast cancer cells: implications for tumor angiogenesis. J Steroid Biochem Mol Biol 144:215–222

    Article  Google Scholar 

  22. Yang B, Miao S, Zhang LN, Sun HB, Xu ZN, Han CS (2015) Correlation of CCNA1 promoter methylation with malignant tumors: a meta-analysis introduction. Biomed Res Int 2015:134027. https://doi.org/10.1155/2015/134027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Klajic J, Busato F, Edvardsen H, Touleimat N, Fleischer T, Bukholm I, Børresen-Dale AL, Lønning PE, Tost J, Kristensen VN (2014) DNA methylation status of key cell-cycle regulators such as CDKNA2/p16 and CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors. Clin Cancer Res 20(24):6357–6366

    Article  CAS  Google Scholar 

  24. Alvarez C, Tapia T, Cornejo V, Fernandez W, Muñoz A, Camus M, Alvarez M, Devoto L, Carvallo P (2013) Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer. Mol Carcinog 52(6):475–487

    Article  CAS  Google Scholar 

  25. Hamadneh L, Al-Majawleh M, Jarrar Y, Shraim S, Hasan M (2018) Culturing conditions highly affect DNA methylation and gene expression levels in MCF7 breast cancer cell line. In Vitro Cell Dev Biol Anim 54(5):331–334

    Article  CAS  Google Scholar 

  26. Kamińska K, Białkowska A, Kowalewski J, Huang S, Lewandowska MA (2019) Differential gene methylation patterns in cancerous and non-cancerous cells. Oncol Rep 42(1):43–54

    PubMed  PubMed Central  Google Scholar 

  27. Hojo T, Masuda N, Iwamoto T, Niikura N, Anan K, Aogi K, Ohnishi T, Yamauchi C, Yoshida M, Kinoshita T, Masuoka H (2020) Taxane-based combinations as adjuvant chemotherapy for node-positive ER-positive breast cancer based on 2004–2009 data from the Breast Cancer Registry of the Japanese Breast Cancer Society. Breast Cancer 27(1):85–91

    Article  Google Scholar 

  28. Yin L, Duan JJ, Bian XW, Yu SC (2020) Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res 22(1):1–3

    Article  Google Scholar 

Download references

Acknowledgements

This project was funded by the Scientific Research Fund/Ministry of Higher Education and Scientific Research, Jordan (MPH/1/20/2017) and Al-Zaytoonah University of Jordan (2019-2018/18/06).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lama Hamadneh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamadneh, L., Abu-Irmaileh, B., Al-Majawleh, M. et al. Doxorubicin–paclitaxel sequential treatment: insights of DNA methylation and gene expression changes of luminal A and triple negative breast cancer cell lines. Mol Cell Biochem 476, 3647–3654 (2021). https://doi.org/10.1007/s11010-021-04191-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-021-04191-5

Keywords

Navigation