TGF-beta signaling in breast cancer
TGF-beta signaling in breast cancer
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DOI：
10.1196/annals.1386.024
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发表时间：
2006-01-01
期刊：
影响因子：
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通讯作者：
Knabbe, Cornelius
中科院分区：
文献类型：
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作者：
Buck, Miriam B.;Knabbe, Cornelius
抗雌激素他莫昔芬是乳腺癌内分泌治疗中最成功的药物之一，能显著降低复发和死亡的风险。抗雌激素通过抑制生长刺激因子的产生以及激活具有生长抑制作用的肽（如转化生长因子 -β（TGF -β））来发挥作用。在激素反应性乳腺癌细胞中，抗雌激素治疗导致TGF -β1转化为具有生物活性的形式。TGF -β2和TGF -β受体（TβR）II的表达是通过涉及p38丝裂原活化蛋白激酶的转录机制诱导的。抑制p38可消除抗雌激素依赖性的生长抑制。然而，TGF -β在乳腺癌进展中的作用是不明确的，因为它既显示出肿瘤抑制作用，又显示出肿瘤促进作用。TGF -β2启动子中的一种多态性可增强该蛋白的表达，且与乳腺癌患者的淋巴结转移有关，这表明TGF -β2在侵袭过程中起作用。一项对乳腺癌组织中TβRI和TβRII表达的免疫组化研究表明，肿瘤的雌激素受体（ER）状态是一个重要的标志物，也是TGF -β从肿瘤抑制因子转变为肿瘤促进因子的潜在介质。在ER阴性肿瘤中，TβRII的表达与一组似乎具有高度侵袭性的肿瘤相关，导致总生存期大幅缩短。对ER表达对TGF -β信号转导影响的进一步研究表明，ER -α在TGF -β信号传导中起着至关重要的作用。
The antiestrogen tamoxifen is one of the most successful drugs in the endocrine treatment of breast cancer and significantly reduces the risk of recurrence and death. Antiestrogens act by inhibiting the production of growth-stimulatory factors as well as by activating peptides with growth-inhibitory effects like transforming growth factor-beta (TGF-beta). In hormone-responsive breast cancer cells treatment with antiestrogens leads to the conversion of TGF-beta 1 into a biologically active form. Expression of TGF-beta 2 and TGF-beta receptor (T beta R) II is induced via a transcriptional mechanism involving p38 MAP kinase. Inhibition of p38 abolishes antiestrogen-dependent growth inhibition. However, the role of TGF-beta in breast cancer progression is ambiguous, as it was shown to display both tumor-suppressing and -enhancing effects. A polymorphism in the promoter of TGF-beta 2 that enhances expression of the protein was associated with lymph node metastasis in breast cancer patients, pointing to a role of TGF-beta 2 in the process of invasion. An immunohistochemical study on T beta RI and T beta RII expression in breast cancer tissues indicates that the estrogen receptor (ER) status of a tumor is an important marker and a potential mediator of the transition of TGF-beta from tumor suppressor to tumor promoter. In ER-negative tumors, expression of T beta RII was associated with a subset of tumors that appeared to be highly aggressive, leading to strongly reduced overall survival times. Further characterization of the influence of ER expression on TGF-beta signal transduction shows that ER-a plays a crucial role in TGF-beta signaling.