Signal transducers and activators of transcription-3 up-regulates tissue inhibitor of metalloproteinase-1 expression and decreases invasiveness of breast cancer
Signal transducers and activators of transcription-3 up-regulates tissue inhibitor of metalloproteinase-1 expression and decreases invasiveness of breast cancer
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DOI：
10.2353/ajpath.2006.051109
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发表时间：
2006-08-01
影响因子：
6
通讯作者：
Lai, Raymond
中科院分区：
文献类型：
--
作者：
Dien, Jennifer;Amin, Hesham M.;Lai, Raymond
信号转导和转录激活因子（STAT）-3是一种致癌蛋白，在许多人类癌症中被组成性激活，包括30%至60%的原发性乳腺癌。乳腺癌中STAT 3激活的生物学意义尚未完全了解。我们之前已经表明，STAT 3上调金属蛋白酶组织抑制剂（TEMP）-1，一种已知阻断金属蛋白酶并降低某些癌细胞类型侵袭性的细胞因子。我们推测STAT 3的激活可能通过调节TIMP 1的表达来调节乳腺癌的侵袭性。使用用四环素关闭的STAT 3C（组成型活性STAT 3）转染的MCF-7细胞，我们产生了一种体外系统，其中STAT 3C水平可以在乳腺癌细胞中被严格控制。增加四环素水平以剂量依赖性方式逐渐降低STAT 3C和TIMP 1，这些蛋白的下调导致这些细胞在Matrigel中的侵袭性的相互降低。在相同的实验系统中，加入中和性抗TIMP 1抗体增加了侵袭性。使用免疫组织化学和142原发性乳腺肿瘤，我们发现磷酸化/活性形式的STAT 3（pSTAT 3）和TIMP 1的表达之间存在显着关联。重要的是，STAT 3激活与较低的血管和淋巴管浸润频率显著相关（分别为P = 0.015和P = 0.0002）。我们的数据支持STAT 3活化显著调节乳腺癌的生物学和临床行为的概念。
Signal transducers and activators of transcription (STAT)-3 is an oncogenic protein that is constitutively activated in many human cancers, including 30 to 60% of primary breast cancer. The biological significance of STAT3 activation in breast cancer is not fully understood. We have previously shown that STAT3 up-regalates tissue inhibitors of metalloproteinase (TEMP)-1, a cytokine known to block metalloproteinases and decrease invasiveness in certain cancer cell types. We hypothesize that STAT3 activation may modulate tumor invasiveness of breast cancer by regulating TIMP1 expression. Using MCF-7 cells transfected with tetracycline-off STAT3C (constitutively active STAT3), we generated an in vitro system in which STAT3C levels can he tightly controlled in breast cancer cells. increasing tetracycline levels gradually decreased STAT3C and TIMP1 in a dose-dependent manner, and down-regulation of these proteins led to a reciprocal decrease in invasive ness of these cells in Matrigel. Addition of a neutralizing anti-TIMP1 antibody increased invasiveness in the same experimental system. Using immunohistochemistry and 142 primary breast tumors, we found a significant association between the expression of the phosphorylated/active form of STAT3 (pSTAT3) and that of TIMP1. importantly, STAT3 activation correlated significantly with a lower frequency of vascular and lymphatic invasion (P = 0.015 and P = 0.0002, respectively). our data support the concept that STAT3 activation significantly modulates the biological and clinical behavior of breast cancer.