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Published on: August 12, 2015
Epigenetic silencing contributes to the loss of BRMS1 expression in breast cancer
Brandon J Metge1, Andra R Frost, Judy A King
1Department of Oncologic Sciences, USA-Mitchell Cancer Institute, University of South Alabama, 307 N. University Blvd., Mobile, AL 36688, USA.
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.
Insights
Breast Cancer Metastasis Suppressor 1 (BRMS1) expression is lost in aggressive breast cancers due to epigenetic silencing. Aberrant methylation of the BRMS1 promoter causes this loss, impacting metastasis suppression.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Breast Cancer Metastasis Suppressor 1 (BRMS1) inhibits metastasis in various cancers.
- BRMS1 is downregulated in breast tumors, particularly in metastatic cases.
- The regulatory mechanisms of BRMS1 expression remain largely unknown.
Purpose of the Study:
- To investigate the epigenetic regulation of BRMS1 expression in breast cancer.
- To identify the cause of BRMS1 downregulation in aggressive breast cancer.
- To establish BRMS1 as a novel target of epigenetic silencing.
Main Methods:
- Analysis of the BRMS1 promoter region using methylation-specific PCR (MSP).
- Examination of CpG island methylation in breast cancer cell lines and patient tissues.
- Correlation of BRMS1 promoter methylation status with BRMS1 expression levels via immunohistochemistry.
Main Results:
- A CpG island in the BRMS1 promoter (-3477 to -2214) was identified.
- This CpG island was hypermethylated in breast cancer cell lines.
- Hypermethylation was observed in 45% of primary tumors and 60% of lymph node metastases.
- A direct correlation was found between BRMS1 promoter hypermethylation and loss of BRMS1 expression.
Conclusions:
- BRMS1 is epigenetically silenced in breast cancer through promoter hypermethylation.
- Aberrant methylation of the BRMS1 promoter is a potential cause for its loss of expression in aggressive breast cancer.
- BRMS1 represents a novel target for epigenetic therapy in breast cancer treatment.
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