Tokunaga Eriko, Oki Eiji, Nishida Kojiro, Koga Tadashi, Yoshida Rintaro, Ikeda Keisuke, Kojima Aya, Egashira Akinori, Morita Masaru, Kakeji Yoshihiro, Maehara Yoshihiko
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Higashi-ku, Japan.
Breast Cancer Res Treat. 2006 May;97(2):199-203. doi: 10.1007/s10549-005-9112-9. Epub 2006 Feb 24.
Taxanes are among the most active agents and they are now known to be an indispensable component in chemotherapy for breast cancer. However, some patients are resistant to taxanes and the identification of the molecular characteristics that can predict the sensitivity to taxanes would be useful in selecting the most appropriate patients to receive taxane therapy. Taxanes are antimicrotubular agents that promote microtubular assembly and stabilize microtubules by preventing depolymerization. They interfere with normal mitotic transition and causes cell cycle arrest in the G2-M metaphase. CHFR (checkpoint with forkhead-associated and ring finger) is a recently identified gene, which functions as an important checkpoint protein early in G2-M transition. Its activation delays the cell cycle in prophase and promotes cell survival in response to the mitotic stress induced by either nocodazole or taxane. CHFR is frequently downregulated in human cancers, mostly owing to the hypermethylation of its promoter region. CHFR downregulation has been found in primary cancers or in the established tumor cells of various origins, such as the lung, colon, esophagus, and stomach. The aberrant hypermethylation of CHFR promoter appears to be a good molecular marker to predict sensitivity to taxanes in gastric, lung, and colon cancer. A downregulation of CHFR was observed in breast cancer cells, however, no apparent promoter hypermethylation has yet been reported. In addition, an alteration of the CHFR expression or aberrant promoter hypermethylation in primary breast cancer has not been fully investigated. In this study, we examined the methylation status of the promoter region of CHFR gene in 110 primary breast cancers. We observed the hypermethylation of the CHFR promoter region in only one case (0.9%). We herein show that the aberrant hypermethylation of this region is quite a rare event in primary breast carcinoma.
紫杉烷类是最有效的药物之一，目前已知它们是乳腺癌化疗中不可或缺的组成部分。然而，一些患者对紫杉烷类耐药，识别能够预测对紫杉烷类敏感性的分子特征，将有助于选择最适合接受紫杉烷类治疗的患者。紫杉烷类是抗微管药物，可促进微管组装并通过防止解聚来稳定微管。它们干扰正常的有丝分裂转变，并导致细胞周期在G2-M中期停滞。CHFR（含叉头相关结构域和环指结构域的检查点蛋白）是最近发现的一个基因，在G2-M转变早期作为一种重要的检查点蛋白发挥作用。其激活会在前期延迟细胞周期，并促进细胞在诺考达唑或紫杉烷诱导的有丝分裂应激下存活。CHFR在人类癌症中经常下调，主要是由于其启动子区域的高甲基化。在原发性癌症或各种来源的已建立肿瘤细胞中，如肺癌、结肠癌、食管癌和胃癌中，均发现了CHFR下调。CHFR启动子的异常高甲基化似乎是预测胃癌、肺癌和结肠癌对紫杉烷类敏感性的良好分子标志物。在乳腺癌细胞中观察到CHFR下调，然而，尚未有明显启动子高甲基化的报道。此外，原发性乳腺癌中CHFR表达的改变或启动子异常高甲基化尚未得到充分研究。在本研究中，我们检测了110例原发性乳腺癌中CHFR基因启动子区域的甲基化状态。我们仅在1例（0.9%）中观察到CHFR启动子区域的高甲基化。我们在此表明，该区域的异常高甲基化在原发性乳腺癌中是相当罕见的事件。
