Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-κB activity
Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-κB activity
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DOI：
10.1158/0008-5472.can-04-3139
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Casey，G
中科院分区：
文献类型：
--
作者：
Cicek，M;Fukuyama，R;Casey，G
乳腺癌转移抑制基因1（BRMS 1）在乳腺癌和黑色素瘤细胞系中作为转移抑制基因发挥作用，但其抑制机制尚不清楚。我们确定BRMS 1的表达与尿激酶型纤溶酶原激活物（uPA）的表达呈负相关，uPA是一种至少部分受核因子-κB（NF-κB）调节的促转移基因。为了进一步研究NF-κB在BRMS 1调控的基因表达中的作用，我们检测了NF-κB结合活性，发现在稳定表达BRMS 1的MDA-MB-231乳腺癌和C8161.9黑色素瘤细胞中，BRMS 1表达与NF-κB结合活性之间呈负相关。相反，BRMS 1表达对激活蛋白-1转录因子的激活没有影响。此外，我们发现BRMS 1抑制组成型和肿瘤坏死因子-α诱导的NF-κB活化可能是由于抑制IκBα磷酸化和降解。为了研究BRMS 1和uPA在原发性乳腺肿瘤中表达的关系，我们筛选了50例乳腺肿瘤和相应正常乳腺组织的标准化cDNA的乳腺癌斑点杂交阵列。BRMS 1 mRNA在乳腺癌组织中的表达明显低于正常乳腺组织（配对t检验，P< 0.0001），且与uPA基因表达呈负相关（P< 0.01）。这些结果表明，BRMS 1依赖性抑制肿瘤转移的潜在机制中至少有一种包括抑制NF-κB活性和随后抑制乳腺癌和黑色素瘤细胞中uPA表达。
Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-κB (NF-κB). To further investigate the role of NF-κB in BRMS1-regulated gene expression, we examined NF-κB binding activity and found an inverse correlation between BRMS1 expression and NF-κB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-α–induced NF-κB activation by BRMS1 may be due to inhibition of IκBα phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction inBRMS1mRNA expression in breast tumors compared with matched normal breast tissues (pairedttest,P< 0.0001) and a general inverse correlation withuPAgene expression (P< 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-κB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells.