Metge Brandon J, Frost Andra R, King Judy A, Dyess Donna Lynn, Welch Danny R, Samant Rajeev S, Shevde Lalita A
Department of Oncologic Sciences, USA-Mitchell Cancer Institute, University of South Alabama, 307 N. University Blvd., Mobile, AL 36688, USA.
Clin Exp Metastasis. 2008;25(7):753-63. doi: 10.1007/s10585-008-9187-x. Epub 2008 Jun 20.
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.
乳腺癌转移抑制因子1（BRMS1）可抑制人乳腺癌、卵巢癌和黑色素瘤在无胸腺小鼠体内的转移。研究还表明，BRMS1在一些乳腺肿瘤中显著下调，尤其是在转移性疾病中。然而，目前尚不清楚调节BRMS1表达的机制。通过甲基化特异性PCR（MSP）分析检测BRMS1启动子区域时，我们发现了一个CpG岛（-3477至-2214），在所有乳腺癌细胞系中均发现该区域存在高甲基化。对20例患者样本进行分析显示，45%的原发性肿瘤和60%的配对淋巴结转移灶中，BRMS1启动子呈现高甲基化。此外，我们发现从组织中分离的DNA中BRMS1启动子的甲基化状态，与通过免疫组织化学评估的BRMS1表达缺失之间存在直接相关性。有多项研究探讨了BRMS1抑制转移的机制；然而，迄今为止，尚无研究报道侵袭性乳腺癌中BRMS1表达缺失的原因。在此，我们首次报道BRMS1是表观遗传沉默的一个新靶点；BRMS1启动子中的异常甲基化可能是其表达缺失的原因。
