Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism.
Prolactin inhibits BCL6 expression in breast cancer through a Stat5a-dependent mechanism.
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DOI：
10.1158/0008-5472.can-09-2314
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Rui H
中科院分区：
文献类型：
--
作者：
Tran TH;Utama FE;Lin J;Yang N;Sjolund AB;Ryder A;Johnson KJ;Neilson LM;Liu C;Brill KL;Rosenberg AL;Witkiewicz AK;Rui H
Stat 5a介导催乳素诱导的乳腺上皮细胞分化，人乳腺癌中Stat 5信号转导的缺失与未分化的组织学和不良预后相关。转录抑制因子BCL 6与Stat 5共享DNA靶序列，破坏乳腺上皮细胞的分化，在哺乳期间下调，在低分化乳腺癌中上调。在这里，我们确定催乳素作为一个有效的抑制BCL 6蛋白表达的人乳腺癌通过一种机制，需要Stat 5a，但不是催乳素激活的Stat 5 b，MEK-ERK，或PI 3 K-AKT途径。催乳素在T47 D、MCF 7、ZR 75. 1和SKBr 3乳腺癌细胞系中迅速抑制BCL 6 mRNA，随后在3 h内延长BCL 6蛋白水平的降低。催乳素抑制BCL 6的增强过表达的Stat 5a，但不是Stat 5 b，模仿组成型活性Stat 5a，但不需要的Stat 5a的反式激活结构域。Stat 5染色质免疫沉淀证实了与BCL 6基因调控区的物理相互作用，并且BCL 6转录抑制需要基于对阿司他丁A的敏感性的组蛋白脱乙酰酶活性。在功能上，BCL 6过表达破坏了Stat 5报告基因的催乳素诱导。BCL 6的催乳素抑制被扩展到裸鼠体内异种移植肿瘤和离体新鲜分离的人乳腺癌外植体。定量免疫组化显示，与DCIS和非恶性乳腺癌相比，高级别和转移性乳腺癌中的BCL 6升高，细胞BCL 6蛋白水平与核Stat 5a呈负相关（r=-0.52; P<0.001），但与Stat 5 b无关。泌乳素-Stat 5a信号传导的丧失和伴随的BCL 6的上调可能代表促进乳腺癌未分化组织学和不良预后的调节开关。
Stat5a mediates prolactin-induced differentiation of mammary epithelia, and loss of Stat5 signaling in human breast cancer is associated with undifferentiated histology and poor prognosis. The transcriptional repressor BCL6 shares DNA target sequences with Stat5, disrupts differentiation of breast epithelia, is down-regulated during lactation, and upregulated in poorly differentiated breast cancer. Here we identify prolactin as a potent suppressor of BCL6 protein expression in human breast cancer through a mechanism that requires Stat5a, but not prolactin-activated Stat5b, MEK-ERK, or PI3K-AKT pathways. Prolactin rapidly suppressed BCL6 mRNA in T47D, MCF7, ZR75.1 and SKBr3 breast cancer cell lines, followed by prolonged reduction of BCL6 protein levels within 3h. Prolactin suppression of BCL6 was enhanced by overexpression of Stat5a but not Stat5b, was mimicked by constitutively active Stat5a, but did not require the transactivation domain of Stat5a. Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes. Prolactin suppression of BCL6 was extended to xenotransplant tumors in nude mice in vivo and to freshly isolated human breast cancer explants ex vivo. Quantitative immunohistochemistry revealed elevated BCL6 in high grade and metastatic breast cancer compared to DCIS and nonmalignant breast, and cellular BCL6 protein levels correlated negatively with nuclear Stat5a (r=−0.52; P<0.001) but not with Stat5b. Loss of prolactin-Stat5a signaling and concomitant upregulation of BCL6 may represent a regulatory switch facilitating undifferentiated histology and poor prognosis of breast cancer.