University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, PA, USA.
J Biol Chem. 2010 Apr 16;285(16):11786-92. doi: 10.1074/jbc.M109.086561. Epub 2010 Feb 25.
The NF-kappaB transcription factor plays a pivotal role in breast cancer progression and therapy resistance. However, the mechanisms by which the tightly regulated NF-kappaB becomes constitutively activated during breast cancer pathogenesis remain obscure. Here, we report that PDZ-LIM domain-containing protein 2 (PDLIM2), an essential terminator of NF-kappaB activation, is repressed in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells, suggesting one important mechanism for the constitutive activation of NF-kappaB. Indeed, PDLIM2 reexpression inhibited constitutive NF-kappaB activation and expression of NF-kappaB-targeted genes in those breast cancer cells. Importantly, PDLIM2, but not its mutants defective in NF-kappaB termination, could suppress in vitro anchorage-independent growth and in vivo tumor formation of those malignant breast cells. In addition, we have shown that PDLIM2 repression involves promoter methylation. Accordingly, treatment of the breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reverses the methylation of the PDLIM2 promoter, restored PDLIM2 expression, and suppressed tumorigenicities of human breast cancer cells both in vitro and in vivo. These studies thus provide important mechanistic insights into breast cancer pathogenesis. These studies also suggest a tumor suppression function of PDLIM2 and a therapeutic strategy for breast cancer.
NF-κB 转录因子在乳腺癌的发生和治疗耐药中起着关键作用。然而，在乳腺癌发病过程中，NF-κB 如何被严格调控而持续激活的机制仍不清楚。在这里，我们报告 PDZ 结构域 LIM 蛋白 2（PDLIM2），NF-κB 激活的一个重要终止子，在雌激素受体阳性和雌激素受体阴性乳腺癌细胞中均受到抑制，提示 NF-κB 持续激活的一个重要机制。事实上，PDLIM2 的重新表达抑制了这些乳腺癌细胞中 NF-κB 的组成性激活和 NF-κB 靶向基因的表达。重要的是，PDLIM2 而非其 NF-κB 终止功能缺陷的突变体，可以抑制这些恶性乳腺癌细胞体外无锚定依赖性生长和体内肿瘤形成。此外，我们已经表明 PDLIM2 的抑制涉及启动子甲基化。相应地，用 DNA 甲基转移酶抑制剂 5-氮杂-2'-脱氧胞苷处理乳腺癌细胞，可逆转 PDLIM2 启动子的甲基化，恢复 PDLIM2 的表达，并抑制人乳腺癌细胞在体外和体内的致瘤性。这些研究为乳腺癌的发病机制提供了重要的机制见解。这些研究还提示 PDLIM2 具有肿瘤抑制功能，并为乳腺癌提供了一种治疗策略。
