Dual effects of TGF-beta on ERalpha-mediated estrogenic transcriptional activity in breast cancer.
Dual effects of TGF-beta on ERalpha-mediated estrogenic transcriptional activity in breast cancer.
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DOI：
10.1186/1476-4598-8-111
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发表时间：
2009-11-27
期刊：
影响因子：
37.3
通讯作者：
Wan M
中科院分区：
文献类型：
--
作者：
Ren Y;Wu L;Frost AR;Grizzle W;Cao X;Wan M
乳腺癌细胞通常会产生 TGF-β 抗性，从而过度产生这种细胞因子，从而创造局部免疫抑制环境，促进肿瘤生长并加剧肿瘤细胞本身的侵袭和转移行为。 Smads 介导的与雌激素受体的相互作用已被暗示在乳腺癌的发生和/或进展中发挥重要作用。我们研究了 TGF-β 如何调节 ERα 诱导的基因转录以及乳腺癌中频繁出现 TGF-β 耐药的潜在机制。使用瞬时转染、实时 PCR、连续 DNA 沉淀和小干扰 RNA 测定，研究了乳腺癌细胞系中 TGF-β 对 ERα 介导的基因转录的影响。通过免疫荧光和免疫组化检测评估 Smads 在人乳腺癌细胞系和 ERα 阳性人乳腺癌组织中的表达。 Smad3/4 复合物介导 TGF-β 对乳腺癌细胞中 ERα 介导的基因转录雌激素活性的抑制，而 Smad4 对于这种抑制是必要且充分的。 Smad3 的过度表达或 Smad4 的抑制都会导致 TGF-β 从阻遏物“转换”为激活物。 Smad4 的下调和异常细胞分布与一些 ERα 阳性浸润性人类乳腺癌有关。从良性乳腺导管组织到浸润性导管癌，Smad4表达呈现动态变化。这些结果表明，Smad4 的异常表达或 Smad4 活性的破坏导致乳腺癌细胞中 TGF-β 对 ERα 反式活性的抑制作用丧失。
TGF-β resistance often develops in breast cancer cells that in turn overproduce this cytokine to create a local immunosuppressive environment that fosters tumor growth and exacerbates the invasive and metastatic behavior of the tumor cells themselves. Smads-mediated cross-talk with the estrogen receptor has been implied to play an important role in development and/or progression of breast cancer. We investigated how TGF-β regulates ERα-induced gene transcription and potential mechanisms of frequent TGF-β resistance in breast cancer. Effect of TGF-β on ERα-mediated gene transcription was investigated in breast cancer cell lines using transient transfection, real-time PCR, sequential DNA precipitation, and small interfering RNA assays. The expression of Smads on both human breast cancer cell lines and ERα-positive human breast cancer tissue was evaluated by immunofluorescence and immunohistochemical assays. A complex of Smad3/4 mediates TGF-β inhibition of ERα-mediated estrogenic activity of gene transcription in breast cancer cells, and Smad4 is essential and sufficient for such repression. Either overexpression of Smad3 or inhibition of Smad4 leads to the "switch" of TGF-β from a repressor to an activator. Down-regulation and abnormal cellular distribution of Smad4 were associated with some ERα-positive infiltrating human breast carcinoma. There appears a dynamic change of Smad4 expression from benign breast ductal tissue to infiltrating ductal carcinoma. These results suggest that aberrant expression of Smad4 or disruption of Smad4 activity lead to the loss of TGF-β suppression of ERα transactivity in breast cancer cells.
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影响因子：
4.8
作者：
Matsuda, T;Yamamoto, T;Saatcioglu, F
通讯作者：
Saatcioglu, F
影响因子：
158.5
作者：
Falini, B;Mecucci, C;Martelli, MF
通讯作者：
Martelli, MF
DOI：
10.1186/bcr1748
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
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作者：
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通讯作者：
Alarid ET
影响因子：
2.8
作者：
Aitchison, Alan A.;Veerakumarasivam, Abhi;Milis, Ian G.
通讯作者：
Milis, Ian G.
影响因子：
--
作者：
Buck, MB;Pfizenmaier, K;Knabbe, C
通讯作者：
Knabbe, C