Methylation-associated silencing of SFRP1 with an 8p11-12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers.
Methylation-associated silencing of SFRP1 with an 8p11-12 amplification inhibits canonical and non-canonical WNT pathways in breast cancers.
复制标题
DOI：
10.1002/ijc.24518
复制
发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Ethier, Stephen P.
中科院分区：
文献类型：
--
作者：
Yang, Zeng-Quan;Liu, Gang;Bollig-Fischer, Aliccia;Haddad, Ramsi;Tarca, Adi L.;Ethier, Stephen P.
最近，我们在一组人乳腺癌细胞系和原代标本中分析了8p11-12基因组区域的拷贝数和基因表达的变化。我们发现，即使在乳腺肿瘤中，SFRP1(分泌型卷曲相关蛋白1)也经常低表达，且该基因组区域的拷贝数增加。SFRP1编码一种WNT信号拮抗剂，在多种实体肿瘤的发生发展中发挥作用。在本研究中，我们用8p11-12扩增子分析了乳腺癌细胞中SFRP1基因甲基化相关的沉默，并研究了SFRP1在乳腺癌细胞中的抑瘤特性。在乳腺癌细胞系和原发肿瘤标本中，与正常原代人乳腺上皮细胞相比，SFRP1的表达显著降低，即使当SFRP1被扩增时也是如此。通过SFRP1基因扩增抑制乳腺癌细胞中SFRP1的表达与SFRP1启动子甲基化有关。此外，SFRP1表达的恢复抑制了乳腺癌细胞的单层生长，并抑制了锚定非依赖性生长。我们还研究了乳腺癌中SFRP1基因沉默与WNT信号转导的关系。乳腺癌细胞中SFRP1的异位表达抑制了规范和非规范的WNT信号通路，并且SFRP1的表达与包括RET和MSX2在内的WNT反应基因的子集的表达呈负相关。因此，SFRP1的下调可由表观遗传和/或遗传事件触发，并可能通过规范和非规范的WNT信号通路促进人类乳腺癌的发生。
Recently we analyzed the 8p11-12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found that SFRP1 (Secreted frizzled related protein 1) is frequently under expressed even in breast tumors with copy number increases in this genomic region. SFRP1 encodes a WNT signaling antagonist, and plays a role in the development of multiple solid tumor types. In this study, we analyzed methylation-associated silencing of the SFRP1 gene in breast cancer cells with the 8p11-12 amplicon, and investigated the tumor suppressor properties of SFRP1 in breast cancer cells. SFRP1 expression was markedly reduced in both the breast cancer cell lines and primary tumor specimens relative to normal primary human mammary epithelial cells even when SFRP1 is amplified. Suppression of SFRP1 expression in breast cancer cells with an SFRP1 gene amplification is associated with SFRP1 promoter methylation. Furthermore, restoration of SFRP1 expression suppressed the growth of breast cancer cells in monolayer, and inhibited anchorage independent growth. We also examined the releationship between the silencing of SFRP1 gene and WNT signaling in breast cancer. Ectopic SFRP1 expression in breast cancer cells suppressed both canonical and non-canonical WNT signaling pathways, and SFRP1 expression was negatively associated with the expression of a subset of WNT responsive genes including RET and MSX2. Thus, down-regulation of SFRP1 can be triggered by epigenetic and/or genetic events and may contribute to the tumorigenesis of human breast cancer through both canonical and non-canonical WNT signaling pathways.
登录
查看更多内容
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
8.8
作者：
Forozan, F;Veldman, R;Ammerman, CA;Parsa, NZ;Kallioniemi, A;Kallioniemi, OP;Ethier, SP
通讯作者：
Ethier, SP
影响因子：
3.7
作者：
Adélaïde, J;Huang, HE;Chaffanet, M
通讯作者：
Chaffanet, M
DOI：
10.1023/b:jomg.0000037157.94207.33
发表时间：
2004-04-01
影响因子：
2.5
作者：
Brennan, KR;Brown, AMC
通讯作者：
Brown, AMC
DOI：
10.1073/pnas.96.16.9212
发表时间：
1999-08-03
影响因子：
11.1
作者：
Perou, CM;Jeffrey, SS;Botstein, D
通讯作者：
Botstein, D