Bilallelic inactivation of retinoic acid receptor β2 gene by epigenetic change in breast cancer

乳腺癌表观遗传变化导致视黄酸受体β2基因双等位基因失活

• 批准号: 14570155
• 负责人: KAKUDO Kennichi
• 金额: $ 2.18万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570155/
• 关键词: breast cancer; retinoic acid receptor β2; point mutation; loss of heterozygosity; chromosome

A growing body of evidence supports the hypotheses that retinoic acid receptor β2 (RAR β2) is a tumor suppressor gene. Although the loss of RAR β2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR β2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR β2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.

越来越多的证据支持视黄酸受体β2（RARβ2）是肿瘤抑制基因的假设。尽管在包括乳腺癌在内的许多恶性肿瘤中已经报道了RARβ2表达的丧失，但分子机制仍然很少了解。我们假设RARβ2活性的丧失可能是由多种因素造成的，包括表观遗传修饰和杂合性丧失（LOH）。使用甲基化特异性聚合酶链反应和LOH分析，我们发现，通过遗传学和父亲等位基因的表观遗传变化或一个等位基因的表观遗传修饰以及剩余等位基因的遗传丧失，可以完全抑制乳腺癌中的RARβ2表达。这是通过抑制基因通过表观遗传机制抑制基因沉默而产生的大量人类癌症，从而使两个等位基因失活。因此，染色质改良剂可以为预防癌症和治疗提供新的策略。

项目成果

Tang W, Taniguchi E, Wang X, Mori I, Kagiya T, Yang Q, Nakmura Y, Nakamura M, Yoshimura G, Sakurai T, Kakudo K.: "Loss of cell cohesion in breast cytology as a characteristic of neuroendocrine carcinoma"Acta Cytol. 46(5). 835-840 (2002)

Tang W、Taniguchi E、Wang X、Mori I、Kagiya T、Yang Q、Nakmura Y、Nakamura M、Yoshimura G、Sakurai T、Kakudo K.：“乳腺细胞学中细胞内聚力丧失是神经内分泌癌的一个特征”Acta

Yang Q, Nakamura Y, Nakamura M, Yoshimura G, Suzuma T, Umemura T, Mori I, Sakurai T, Kakudo K.: "Loss of Msh2 is not associated with FHIT deletion in breast carcinomas"Anticancer Res. 22(5). 2591-2595 (2002)

Yang Q、Nakamura Y、Nakamura M、Yoshimura G、Suzuma T、Umemura T、Mori I、Sakurai T、Kakudo K.：“Msh2 的丢失与乳腺癌中的 FHIT 缺失无关”Anticancer Res。

Yang Q, Shan L, Yoshimura G, Nakamura M, Nakamura Y, Suzuma T, Umemura T, Mori I, Sakurai T, Kakudo K.: "5-aza-2'-deoxycytidine induces retinoic acid receptor beta 2 demethylation, cell cycle arrest and growth inhibition in breast carcinoma cells"Anticanc

Yang Q、Shan L、Yoshimura G、Nakamura M、Nakamura Y、Suzuma T、Umemura T、Mori I、Sakurai T、Kakudo K.：“5-aza-2-脱氧胞苷诱导视黄酸受体 β 2 去甲基化、细胞周期

Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K.: "endothelial growth factor-d expression, nodal status, and prognosis in breast cancer"Clin Cancer Res.. 9(14). 5313-5317 (2003)

Nakamura Y、Yasuoka H、Tsujimoto M、Yang Q、Imabun S、Nakahara M、Nakao K、Nakamura M、Mori I、Kakudo K.：“乳腺癌中的内皮生长因子-d 表达、淋巴结状态和预后”临床癌症

Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K: "Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer/"Clin Can

Nakamura Y、Yasuoka H、Tsujimoto M、Yang Q、Imabun S、Nakahara M、Nakao K、Nakamura M、Mori I、Kakudo K：“Flt-4 阳性血管密度与血管内皮生长因子-d 表达、淋巴结状态相关