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

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

Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell’s Journey

“…This observation has led to exploration of the promoter methylation patterns for the metastasis suppressors. The BRMS1 promoter contains several CpG islands which can become methylated and effect gene expression [34]. Chimonidou et al recently assessed CTC from breast cancer patients for BRMS1 expression and BRMS1 promoter methylation and found that reduced expression and promoter methylation correspond to probability of recurrence from metastasis and survival [35].…”

BRMS1 (breast cancer metastasis suppressor 1)

“…Structural analysis of the BRMS1 promoter has revealed the presence of two hypermethylated cytosinephosphoguanine (CpG) islands (Metge et al, 2008). Hypermethylation of CpG islands restricts the activity of the BRMS1 protein, mainly due the tightly packed nucleosomes (Metge et al, 2008).…”

“…Hypermethylation of CpG islands restricts the activity of the BRMS1 protein, mainly due the tightly packed nucleosomes (Metge et al, 2008). Gene expression can also be suppressed by blocking transcription factor binding.…”

“…In addition, BRMS1 has been shown to negatively regulate NF-kB activity, which is constitutively activated in many human cancers and plays an important role in apoptosis (Samant et al, 2007). Metge et al (2008) recently identified two hypermethylated CpG islands in the BRMS1 promoter. This group also observed reduced expression of BRMS1 in metastatic breast cancer cell lines.…”

The application of circulating tumor cells detecting methods in veterinary oncology

“…For several years the extensive research carried out on the mechanisms of metastases formation concentrated on circulating tumor cells(CTC). The modern understanding of cancer biology and process of metastasis suggest that these circulating cells play a vital role in forming metastatic disease (Metge et al 2008).…”