Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer
Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer
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DOI：
10.1007/s12282-011-0272-7
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发表时间：
2012-07-01
期刊：
影响因子：
4
通讯作者：
Murakami, Yoshinori
中科院分区：
文献类型：
--
作者：
Takahashi, Yuka;Iwai, Miwako;Murakami, Yoshinori
在非小细胞肺癌中，抑癌基因 CADM1/TSLC1 和 DAL-1/4.1B 经常因启动子甲基化而失活。它们编码的蛋白质 CADM1 和 4.1B 在人类上皮细胞中形成复合物，并参与细胞间粘附。通过免疫组织化学方法在 67 个原发性乳腺癌和邻近非癌组织中检查了 CADM1 和 4.1B 蛋白质的表达。通过逆转录聚合酶链反应（RT-PCR）检测CADM1和4.1B信使RNA（mRNA）。通过亚硫酸氢盐处理和焦磷酸测序定量测定 CADM1 和 4.1B 启动子的甲基化状态。在正常乳腺上皮细胞中沿细胞膜检测到 CADM1 和 4.1B 蛋白信号。相比之下，67 例原发性乳腺癌中，分别有 47 例 (70%) 和 49 例 (73%) 显示异常 CADM1 和 4.1B 染色。异常 CADM1 染色更常见于 pT2 和 pT3 肿瘤以及 II 期和 III 期肿瘤（分别为 P = 0.045 和 P = 0.020），而异常 4.1B 染色更常见于有淋巴结转移的肿瘤、pT2 和 pT3 肿瘤以及 II 期和 III 期肿瘤（P = 0.0058、P = 0.0098 和 P = 0.0007，分别）。此外，相对于同一标本的非侵袭性病变，异常的 CADM1 和 4.1B 表达优先在侵袭性病变中观察到（分别为 P = 0.036 和 P = 0.0009）。最后，分别在 46% 和 42% 的原发性乳腺癌中检测到 CADM1 和 4.1B 基因的高甲基化。我们的研究结果表明，异常的 CADM1 和 4.1B 表达与乳腺癌的进展有关，尤其是侵袭间质和转移。
The tumor suppressor genes CADM1/TSLC1 and DAL-1/4.1B are frequently inactivated by promoter methylation in non-small cell lung cancer. The proteins they encode, CADM1 and 4.1B, form a complex in human epithelial cells and are involved in cell-cell adhesion.Expression of CADM1 and 4.1B proteins was examined by immunohistochemistry in 67 primary breast cancer and adjacent noncancerous tissues. CADM1 and 4.1B messenger RNA (mRNA) was detected by reverse-transcription polymerase chain reaction (RT-PCR). The methylation status of the CADM1 and 4.1B promoters was determined quantitatively by bisulfite treatment followed by pyrosequencing.CADM1 and 4.1B protein signals were detected along the cell membrane in normal mammary epithelia. By contrast, 47 (70%) and 49 (73%) of 67 primary breast cancers showed aberrant CADM1 and 4.1B staining, respectively. Aberrant CADM1 staining was more frequently observed in pT2 and pT3 tumors and for stages II and III (P = 0.045 and P = 0.020, respectively), while aberrant 4.1B staining was more often observed in tumors with lymph node metastasis, for pT2 and pT3 tumors, and for stages II and III (P = 0.0058, P = 0.0098, and P = 0.0007, respectively). Furthermore, aberrant CADM1 and 4.1B expression was preferentially observed in invasive relative to noninvasive lesions from the same specimen (P = 0.036 and P = 0.0009, respectively). Finally, hypermethylation of CADM1 and 4.1B genes was detected in 46% and 42% of primary breast cancers, respectively.Our findings suggest that aberrant CADM1 and 4.1B expression is involved in progression of breast cancer, especially in invasion into the stroma and metastasis.