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Clinical & Experimental Metastasis

, Volume 25, Issue 7, pp 753–763 | Cite as

Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer

  • Brandon J. Metge
  • Andra R. Frost
  • Judy A. King
  • Donna Lynn Dyess
  • Danny R. Welch
  • Rajeev S. Samant
  • Lalita A. Shevde
Research Paper

Abstract

Breast Cancer Metastasis Suppressor 1 (BRMS1) suppresses metastasis of human breast cancer, ovarian cancer and melanoma in athymic mice. Studies have also shown that BRMS1 is significantly downregulated in some breast tumors, especially in metastatic disease. However, the mechanisms which regulate BRMS1 expression are currently unknown. Upon examination of the BRMS1 promoter region by methylation specific PCR (MSP) analysis, we discovered a CpG island (−3477 to −2214), which was found to be hypermethylated across breast cancer cell lines. A panel of 20 patient samples analyzed showed that 45% of the primary tumors and 60% of the matched lymph node metastases, displayed hypermethylation of BRMS1 promoter. Furthermore, we found a direct correlation between the methylation status of the BRMS1 promoter in the DNA isolated from tissues, with the loss of BRMS1 expression assessed by immunohistochemistry. There are several studies investigating the mechanism by which BRMS1 suppresses metastasis; however thus far there is no study that reports the cause(s) of loss of BRMS1 expression in aggressive breast cancer. Here we report for the first time that BRMS1 is a novel target of epigenetic silencing; and aberrant methylation in the BRMS1 promoter may serve as a cause of loss of its expression.

Keywords

BRMS1 Methylation Epigenetic silencing CpG island 

Abbreviations

5-aza-dC

5-Aza-2′-deoxycytidine

BGS

Bisulfite genomic sequencing

BRMS1

Breast Cancer Metastasis Suppressor

IDV

Integrated density value

LN Met

Metastatic breast cancer cells that metastasized to the lymph node

MSP

Methylation specific PCR

TE

Tris–EDTA

Notes

Acknowledgments

This work was supported by grants BCTR0402317 (LAS) and BCTR0503488 (RSS) from Susan G. Komen for the Cure and CA88728 (DRW) and CA89019 (DRW, ARF, LRS, RSS), National Foundation for Cancer Research (DRW, ARF).

Supplementary material

10585_2008_9187_MOESM1_ESM.doc (23 kb)
MOESM1 (DOC 11 kb)
10585_2008_9187_MOESM2_ESM.ppt (153 kb)
MOESM2 (PPT 153 kb)

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Brandon J. Metge
    • 1
  • Andra R. Frost
    • 2
  • Judy A. King
    • 3
    • 4
  • Donna Lynn Dyess
    • 5
  • Danny R. Welch
    • 2
    • 6
  • Rajeev S. Samant
    • 1
  • Lalita A. Shevde
    • 1
  1. 1.Department of Oncologic Sciences, USA-Mitchell Cancer InstituteUniversity of South AlabamaMobileUSA
  2. 2.Department of PathologyUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Department of PharmacologyUniversity of South AlabamaMobileUSA
  4. 4.Department of PathologyUniversity of South AlabamaMobileUSA
  5. 5.Department of SurgeryUniversity of South AlabamaMobileUSA
  6. 6.NFCR-Center for Metastasis ResearchUniversity of Alabama at BirminghamBirminghamUSA

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