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Tumor Biology

, Volume 36, Issue 12, pp 9677–9683 | Cite as

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

  • Ashraf Dallol
  • Abdelbaset Buhmeida
  • Adnan Merdad
  • Jaudah Al-Maghrabi
  • Mamdooh A. Gari
  • Muhammad M. Abu-Elmagd
  • Aisha Elaimi
  • Mourad Assidi
  • Adeel G. Chaudhary
  • Adel M. Abuzenadah
  • Taoufik Nedjadi
  • Eramah Ermiah
  • Shadi S. Alkhayyat
  • Mohammed H. Al-Qahtani
Research Article

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.

Keywords

Breast cancer Methylation KLOTHO FGFR4 FGF19 

Notes

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

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Ashraf Dallol
    • 1
    • 2
  • Abdelbaset Buhmeida
    • 1
  • Adnan Merdad
    • 3
  • Jaudah Al-Maghrabi
    • 4
  • Mamdooh A. Gari
    • 1
    • 5
  • Muhammad M. Abu-Elmagd
    • 1
    • 8
  • Aisha Elaimi
    • 2
    • 5
  • Mourad Assidi
    • 1
  • Adeel G. Chaudhary
    • 1
    • 5
  • Adel M. Abuzenadah
    • 1
    • 2
    • 5
  • Taoufik Nedjadi
    • 6
  • Eramah Ermiah
    • 7
  • Shadi S. Alkhayyat
    • 9
  • Mohammed H. Al-Qahtani
    • 1
    • 5
  1. 1.Center of Excellence in Genomic Medicine ResearchKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  2. 2.KACST Technology Innovation Center in Personalized MedicineKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  3. 3.Department of Surgery, Faculty of MedicineKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  4. 4.Department of Pathology, Faculty of MedicineKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  5. 5.Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  6. 6.King Fahd Medical Research CenterKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia
  7. 7.Department of OncologyNational Cancer InstituteSabrathaLibya
  8. 8.Faculty of Science, Zoology DepartmentMinia UniversityMiniaEgypt
  9. 9.King Abdulaziz University HospitalJeddahKingdom of Saudi Arabia

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