Activated Abl kinase inhibits oncogenic transforming growth factor-β signaling and tumorigenesis in mammary tumors
Activated Abl kinase inhibits oncogenic transforming growth factor-β signaling and tumorigenesis in mammary tumors
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DOI：
10.1096/fj.09-138412
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发表时间：
2009-12-01
期刊：
影响因子：
4.8
通讯作者：
Schiemann, William P.
中科院分区：
文献类型：
--
作者：
Allington, Tressa M.;Galliher-Beckley, Amy J.;Schiemann, William P.
转化生长因子-β是一种普遍存在的细胞因子，具有抑制和促进肿瘤生长的双重作用，这两种作用阻碍了转化生长因子-β靶向肿瘤信号转导治疗的发展。相比之下，Abl被公认为是造血癌的启动者；然而，Abl在调节实体肿瘤发展中的明确作用仍然难以捉摸。在这里，我们研究了Abl在转化生长因子-β介导的正常和转移乳腺上皮细胞(MECs)上皮-间充质转化(EMT)中的作用。在此过程中，我们发现Abl是MEC形态的重要调节因子，并表明Abl失活足以在正常MEC中诱导表型和转录的EMT。转移性微血管内皮细胞Abl活性增强可使其形态完全逆转，恢复对转化生长因子-β的细胞抑制反应，并阻断转化生长因子-β诱导的基质金属蛋白酶分泌。结构性活跃的Abl表达阻止了转化生长因子-β反应的小鼠乳腺肿瘤的生长，而伊马替尼治疗对携带乳腺肿瘤的小鼠没有临床益处。总而言之，这项研究确立了Abl是MEC身份的有效中介，并在乳腺肿瘤发生过程中抑制了致癌的转化生长因子-β信号。值得注意的是，我们的发现强烈警告不要使用药物Abl拮抗剂来治疗发展和进展中的乳腺肿瘤。-Allington，T.M.，Galliher-Beckley，A.J.，Schiemann，W.P.激活的Abl激酶抑制乳腺癌中的致癌转化生长因子-β信号转导和肿瘤发生。FASE B J.23,4231-4243(2009)。Www.fasebj.org
Transforming growth factor-beta (TGF-beta) is a ubiquitous cytokine with dual roles in tumor suppression and promotion, and these dichotomous functions have frustrated the development of therapies targeting oncogenic signaling by TGF-beta. In comparison, Abl is well established as an initiator of hematopoietic cancers; however, a clear role for Abl in regulating solid tumor development remains elusive. Here, we investigated the role of Abl in TGF-beta-mediated epithelial-mesenchymal transition (EMT) in normal and metastatic mammary epithelial cells (MECs). In doing so, we identified Abl as an essential regulator of MEC morphology and showed that Abl inactivation was sufficient to induce phenotypic and transcriptional EMT in normal MECs. Increasing Abl activity in metastatic MECs resulted in their complete morphological reversion, restored their cytostatic response to TGF-beta, and blocked their secretion of matrix metalloproteinases induced by TGF-beta. Constitutively active Abl expression blocked TGF-beta-responsive mammary tumor growth in mice, while Imatinib therapy afforded no clinical benefit in mice bearing mammary tumors. Collectively, this investigation establishes Abl as a potent mediator of MEC identity, and as a suppressor of oncogenic TGF-beta signaling during mammary tumorigenesis. Notably, our findings strongly caution against the use of pharmacological Abl antagonists in the treatment of developing and progressing mammary tumors.-Allington, T. M., Galliher-Beckley, A. J., Schiemann, W. P. Activated Abl kinase inhibits oncogenic transforming growth factor-beta signaling and tumorigenesis in mammary tumors. FASEB J. 23, 4231-4243 (2009). www.fasebj.org