Skip to main content

Advertisement

SpringerLink
Log in

Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast

  • Research Article
  • Published:
Tumor Biology

Abstract

Invasive ductal carcinoma of the breast is the most common cancer affecting women worldwide. The marked heterogeneity of breast cancer is matched only with the heterogeneity in its associated or causative factors. Breast cancer in Saudi Arabia is apparently an early onset with many of the affected females diagnosed before they reach the age of 50 years. One possible rationale underlying this observation is that consanguinity, which is widely spread in the Saudi community, is causing the accumulation of yet undetermined cancer susceptibility mutations. Another factor could be the accumulation of epigenetic aberrations caused by the shift toward a Western-like lifestyle in the past two decades. In order to shed some light into the molecular mechanisms underlying breast cancer in the Saudi community, we identified KLOTHO (KL) as a tumor-specific methylated gene using genome-wide methylation analysis of primary breast tumors utilizing the MBD-seq approach. KL methylation was frequent as it was detected in 55.3 % of breast cancer cases from Saudi Arabia (n = 179) using MethyLight assay. Furthermore, KL is downregulated in breast tumors with its expression induced following treatment with 5-azacytidine. The involvement of KL in breast cancer led us to investigate its relationship in the context of breast cancer, with one of the protagonists of its function, fibroblast growth factor receptor 4 (FGFR4). Overexpression of FGFR4 in breast cancer is frequent in our cohort and this overexpression is associated with poor overall survival. Interestingly, FGFR4 expression is higher in the absence of KL methylation and lower when KL is methylated and presumably silenced, which is suggestive of an intricate relationship between the two factors. In conclusion, our findings further implicate “metabolic” genes or pathways in breast cancer that are disrupted by epigenetic mechanisms and could provide new avenues for understanding this disease in a new context.

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

Similar content being viewed by others

References

  1. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet. 2011;378:1461–84.

    Article  PubMed  Google Scholar 

  2. Mehmood A, Te OB, Urcia JC, Khan A. Tumor registry annual report. Saudi Arabia: King Faisal Specialist Hospital & Research Center; 2011.

    Google Scholar 

  3. Najjar H, Easson A. Age at diagnosis of breast cancer in Arab nations. Int J Surg. 2010;8:448–52.

    Article  PubMed  Google Scholar 

  4. CRUK. Cancerstats. UK: Cancer Research UK; 2014. http://www.cancerresearchuk.org/health-professional/cancer-statistics, Accessed March 2014.

  5. Merdad A, Gari MA, Hussein S, Al-Khayat S, Tashkandi H, Al-Maghrabi J, et al. Characterization of familial breast cancer in Saudi Arabia. BMC Genomics. 2015;16:S3.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Buhmeida A, Dallol A, Merdad A, Al-Maghrabi J, Gari MA, Abu-Elmagd MM, et al. High fibroblast growth factor 19 (fgf19) expression predicts worse prognosis in invasive ductal carcinoma of breast. Tumor Biol. 2014;35:2817–24.

    Article  CAS  Google Scholar 

  7. Kuro-o M. Klotho in health and disease. Curr Opin Nephrol Hypertens. 2012;21:362–8.

    Article  CAS  PubMed  Google Scholar 

  8. Masuda H, Chikuda H, Suga T, Kawaguchi H, Kuro-o M. Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice. Mech Ageing Dev. 2005;126:1274–83.

    Article  CAS  PubMed  Google Scholar 

  9. Xu Y, Sun Z. Molecular basis of klotho: from gene to function in aging. Endocr Rev. 2015;36:174–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281:6120–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, et al. Klotho: a tumor suppressor and a modulator of the igf-1 and fgf pathways in human breast cancer. Oncogene. 2008;27:7094–105.

    Article  CAS  PubMed  Google Scholar 

  12. Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem. 2008;389:233–41.

    Article  CAS  PubMed  Google Scholar 

  13. Ravikumar P, Ye J, Zhang J, Pinch SN, Hu MC, Kuro-o M, et al. Alpha-klotho protects against oxidative damage in pulmonary epithelia. Am J Physiol Lung Cell Mol Physiol. 2014;307:L566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen CD, Li H, Liang J, Hixson K, Zeldich E, Abraham CR. The anti-aging and tumor suppressor protein klotho enhances differentiation of a human oligodendrocytic hybrid cell line. J Mol Neurosci. 2015;55:76–90.

    Article  CAS  PubMed  Google Scholar 

  15. Lee J, Jeong DJ, Kim J, Lee S, Park JH, Chang B, et al. The anti-aging gene klotho is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer. 2010;9:109.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pan J, Zhong J, Gan LH, Chen SJ, Jin HC, Wang X, et al. Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumour Biol. 2011;32:729–35.

    Article  CAS  PubMed  Google Scholar 

  17. Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta. 2013;424:53–65.

    Article  CAS  PubMed  Google Scholar 

  18. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, et al. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat. 2012;133:649–57.

    Article  CAS  PubMed  Google Scholar 

  19. Wang L, Wang X, Wang X, Jie P, Lu H, Zhang S, et al. Klotho is silenced through promoter hypermethylation in gastric cancer. Am J Cancer Res. 2011;1:111–9.

    CAS  PubMed  Google Scholar 

  20. Xie B, Zhou J, Yuan L, Ren F, Liu DC, Li Q, et al. Epigenetic silencing of klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum Pathol. 2013;44:795–801.

    Article  CAS  PubMed  Google Scholar 

  21. Martin A, David V, Quarles LD. Regulation and function of the fgf23/klotho endocrine pathways. Physiol Rev. 2012;92:131–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical fgf receptor into a specific receptor for fgf23. Nature. 2006;444:770–4.

    Article  CAS  PubMed  Google Scholar 

  23. Liu R, Li J, Xie K, Zhang T, Lei Y, Chen Y, et al. Fgfr4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer. Cancer Res. 2013;73:5926–35.

    Article  CAS  PubMed  Google Scholar 

  24. Luo Y, Yang C, Ye M, Jin C, Abbruzzese JL, Lee MH, et al. Deficiency of metabolic regulator fgfr4 delays breast cancer progression through systemic and microenvironmental metabolic alterations. Cancer Metab. 2013;1:21.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Marme F, Werft W, Benner A, Burwinkel B, Sinn P, Sohn C, et al. Fgfr4 arg388 genotype is associated with pathological complete response to neoadjuvant chemotherapy for primary breast cancer. Ann Oncol. 2010;21:1636–42.

    Article  CAS  PubMed  Google Scholar 

  26. Xu B, Tong N, Chen SQ, Hua LX, Wang ZJ, Zhang ZD, et al. Fgfr4 gly388arg polymorphism contributes to prostate cancer development and progression: a meta-analysis of 2618 cases and 2305 controls. BMC Cancer. 2011;11:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of chip-seq (macs). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Salmon-Divon M, Dvinge H, Tammoja K, Bertone P. PeakAnalyzer: genome-wide annotation of chromatin binding and modification loci. BMC Bioinformatics. 2010;11:415.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dallol A, Al-Ali W, Al-Shaibani A, Al-Mulla F. Analysis of DNA methylation in ffpe tissues using the MethyLight technology. Methods Mol Biol. 2011;724:191–204.

  31. Abu-Elmagd M, Ishii Y, Cheung M, Rex M, Le Rouedec D, Scotting PJ. Csox3 expression and neurogenesis in the epibranchial placodes. Dev Biol. 2001;237:258–69.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like thank the Ministry of Education and King Abdulaziz City for Science and Technology (KACST) for their financial support to this research project (ARP-29-292).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia

    Ashraf Dallol, Abdelbaset Buhmeida, Mamdooh A. Gari, Muhammad M. Abu-Elmagd, Mourad Assidi, Adeel G. Chaudhary, Adel M. Abuzenadah & Mohammed H. Al-Qahtani

  2. KACST Technology Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Ashraf Dallol, Aisha Elaimi & Adel M. Abuzenadah

  3. Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Adnan Merdad

  4. Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Jaudah Al-Maghrabi

  5. Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Mamdooh A. Gari, Aisha Elaimi, Adeel G. Chaudhary, Adel M. Abuzenadah & Mohammed H. Al-Qahtani

  6. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Taoufik Nedjadi

  7. Department of Oncology, National Cancer Institute, Sabratha, Libya

    Eramah Ermiah

  8. Faculty of Science, Zoology Department, Minia University, Minia, Egypt

    Muhammad M. Abu-Elmagd

  9. King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia

    Shadi S. Alkhayyat

Authors
  1. Ashraf Dallol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abdelbaset Buhmeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adnan Merdad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jaudah Al-Maghrabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mamdooh A. Gari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Muhammad M. Abu-Elmagd
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aisha Elaimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mourad Assidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adeel G. Chaudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Adel M. Abuzenadah
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Taoufik Nedjadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eramah Ermiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shadi S. Alkhayyat
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mohammed H. Al-Qahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashraf Dallol.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dallol, A., Buhmeida, A., Merdad, A. et al. Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast. Tumor Biol. 36, 9677–9683 (2015). https://doi.org/10.1007/s13277-015-3733-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3733-3

Keywords

Search

Navigation