Skip to main content

Advertisement

SpringerLink
Log in

PI3K/AKT and MAPK1 molecular changes preceding matrix metallopeptidases overexpression during tamoxifen-resistance development are correlated to poor prognosis in breast cancer patients

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Metastasis and drug resistance remain a persistent key clinical obstacle to the success of breast cancer treatments. Recent years have seen an increased focus on understanding the factors that influence metastasis and drug resistance.

Methods

In this study, the changes in MMPs gene expression were investigated together with their regulatory pathways—PI3K, MAPK and NFKβ pathways—during the process of developing tamoxifen resistance in MCF7 cell line. Gene correlation maps and Kaplan–Meier survival plots among all breast cancer patients and patients treated with tamoxifen were evaluated.

Results

MMPs gene expression was found to be up regulated in MCF7 cell line treated with tamoxifen during the development of tamoxifen resistance using two approaches. Up-regulation of gene expression of AKT1 and MAPK1 started in cells treated with 10 μM tamoxifen that was followed with up-regulation of other genes in these pathways and MMPs in cells treated with 35 μM tamoxifen. MMPs and genes from PI3K, MAPK and NFKβ pathways showed highly significant increase of expression at 50 μM or when cells were treated sequentially six times with 35 μM. Furthermore, increased genes expression was associated with aggressive pattern, clear morphological changes, higher growth rate, increased migration and adhesion potential and tamoxifen insensitivity. Breast cancer distant metastasis-free survival, and survival among tamoxifen treated patients had high expression levels of MAPK1, AKT1, TIMP2, MMP1, and MMP9 showed poor prognosis.

Conclusion

Early changes of MAPK1, AKT1 gene expression upon tamoxifen treatment could possibly be used as an early marker of resistance and future poor prognosis.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Makki J. Diversity of breast carcinoma: histological subtypes and clinical relevance. Clin Med Insights Pathol. 2015;8:23–31. https://doi.org/10.4137/CPath.S31563.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321:288–300.

    Article  CAS  Google Scholar 

  3. Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular classification of breast carcinoma: from traditional, old-fashioned way to a new age, and a new way. J Breast Health. 2015;11:59–66.

    Article  Google Scholar 

  4. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. JNCI J Natl Cancer Inst. 2009;101:736–50.

    Article  CAS  Google Scholar 

  5. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1–24.

    Article  CAS  Google Scholar 

  6. Araki K, Miyoshi Y. Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer. 2018;5:392–401.

    Article  Google Scholar 

  7. AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor–positive breast cancer. Curr Oncol. 2018;25(Suppl 1):S18–27.

    Article  CAS  Google Scholar 

  8. Wilson S, Chia SK. Treatment algorithms for hormone receptor-positive advanced breast cancer: applying the results from recent clinical trials into daily practice—insights, limitations, and moving forward. Am Soc Clin Oncol Educ Book. 2013;33:e20–7.

    Article  Google Scholar 

  9. Haque M, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol. 2019;10:573.

    Article  Google Scholar 

  10. Heiney SP, Parker PD, Felder TM, Adams SA, Omofuma OO, Hulett JM. A systematic review of interventions to improve adherence to endocrine therapy. Breast Cancer Res Treat. 2019;173:499–510.

    Article  Google Scholar 

  11. Hamadneh L, Abuarqoub R, Alhusban A, Bahader M. Upregulation of PI3K/AKT/PTEN pathway is correlated with glucose and glutamine metabolic dysfunction during tamoxifen resistance development in MCF-7 cells. Sci Rep. 2020;10(1):1–7. https://doi.org/10.1038/s41598-020-78833-x.

    Article  CAS  Google Scholar 

  12. Kastrati I, Joosten SE, Semina SE, Alejo LH, Brovkovych SD, Stender JD, et al. The NFκB pathway promotes tamoxifen tolerance and disease recurrence in estrogen receptor positive breast cancers. Mol Cancer Res. 2020;18:1018–27.

    Article  CAS  Google Scholar 

  13. Xu W, Yang Z, Lu N. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9:317–24.

    Article  CAS  Google Scholar 

  14. Roy R, Morad G, Jedinak A, Moses MA. Metalloproteinases and their roles in human cancer. Anat Rec. 2020;303:1557–72.

    Article  CAS  Google Scholar 

  15. Abedin M, King N. Diverse evolutionary paths to cell adhesion. Trends Cell Biol. 2010;20:734–42.

    Article  CAS  Google Scholar 

  16. Wang Q, Gun M, Hong XY. Induced tamoxifen resistance is mediated by increased methylation of e-cadherin in estrogen receptor-expressing breast cancer cells. Sci Rep. 2019;9:1–7.

    Google Scholar 

  17. Györffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1809 patients. Breast Cancer Res Treat. 2010;123:725–31.

    Article  Google Scholar 

  18. Shen CJ, Kuo YL, Chen CC, Chen MJ, Cheng YM. MMP1 expression is activated by Slug and enhances multi-drug resistance (MDR) in breast cancer. PLoS ONE. 2017;12:e0174487.

    Article  Google Scholar 

  19. Jiang Q, Pan Y, Cheng Y, Li H, Liu D, Li H. Lunasin suppresses the migration and invasion of breast cancer cells by inhibiting matrix metalloproteinase-2/-9 via the FAK/Akt/ERK and NF-κB signaling pathways. Oncol Rep. 2016;36:253–62.

    Article  CAS  Google Scholar 

  20. Chung TW, Choi H, Lee JM, Ha SH, Kwak CH, Abekura F, et al. Oldenlandia diffusa suppresses metastatic potential through inhibiting matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression via p38 and ERK1/2 MAPK pathways and induces apoptosis in human breast cancer MCF-7 cells. J Ethnopharmacol. 2017;195:309–17.

    Article  CAS  Google Scholar 

  21. Zhuang S, Li L, Zang Y, Li G, Wang F. RRM2 elicits the metastatic potential of breast cancer cells by regulating cell invasion, migration and VEGF expression via the PI3K/AKT signaling. Oncol Lett. 2020;19:3349–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang H, Liang J, Zhou J, Mi J, Ma K, Fan Y, et al. Knockdown of RHOC by shRNA suppresses invasion and migration of cholangiocellular carcinoma cells via inhibition of MMP2, MMP3, MMP9 and epithelial-mesenchymal transition. Mol Med Rep. 2016;13:5255–61.

    Article  CAS  Google Scholar 

  23. Joseph C, Alsaleem M, Orah N, Narasimha PL, Miligy IM, Kurozumi S, et al. Elevated MMP9 expression in breast cancer is a predictor of shorter patient survival. Breast Cancer Res Treat. 2020;182:267–82.

    Article  CAS  Google Scholar 

  24. Wang QM, Lv L, Tang Y, Zhang L, Wang LF. MMP-1 is overexpressed in triple-negative breast cancer tissues and the knockdown of MMP-1 expression inhibits tumor cell malignant behaviors in vitro. Oncol lett. 2019;17:1732–40.

    CAS  PubMed  Google Scholar 

  25. Li H, Qiu Z, Li F, Wang C. The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncol lett. 2017;14:5865–70.

    PubMed  PubMed Central  Google Scholar 

  26. Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015;44:247–54.

    Article  Google Scholar 

  27. Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer. 2017;17:38–53.

    Article  CAS  Google Scholar 

  28. Qin L, Wang Y, Yang N, Zhang Y, Zhao T, Wu Y, et al. Tissue inhibitor of metalloproteinase-1 (TIMP-1) as a prognostic biomarker in gastrointestinal cancer: a meta-analysis. PeerJ. 2021;9:e10859.

    Article  Google Scholar 

  29. Hekmat O, Munk S, Fogh L, Yadav R, Francavilla C, Horn H, et al. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. J Proteome Res. 2013;12:4136–51.

    Article  CAS  Google Scholar 

  30. Remacle A, McCarthy K, Noël A, Maguire T, McDermott E, Ohiggins N, et al. High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer. 2000;89(2):118–21.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This project was funded by Al-Zaytoonah University of Jordan research funds (2019–2018/18/06) and (2020–2019/23/06).

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, AL-Zaytoonah University of Jordan, Amman, 11733, Jordan

    Lama Hamadneh, Mohamad Bahader, Rama Abuarqoub, Ala Alhusban & Suhair Hikmat

  2. Leibniz-Institut Für Analytische Wissenschaften - ISAS - e.v, Bunsen-Kirchhoff-Straße 11, 44139, Dortmund, Germany

    Mohammad AlWahsh

  3. Institute of Pathology and Medical Research Center (ZMF), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany

    Mohammad AlWahsh

Authors
  1. Lama Hamadneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamad Bahader
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rama Abuarqoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad AlWahsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ala Alhusban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suhair Hikmat
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamadneh, L., Bahader, M., Abuarqoub, R. et al. PI3K/AKT and MAPK1 molecular changes preceding matrix metallopeptidases overexpression during tamoxifen-resistance development are correlated to poor prognosis in breast cancer patients. Breast Cancer 28, 1358–1366 (2021). https://doi.org/10.1007/s12282-021-01277-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-021-01277-2

Keywords

Search

Navigation