Department of Pharmacology, MS-8303, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
FASEB J. 2009 Dec;23(12):4231-43. doi: 10.1096/fj.09-138412. Epub 2009 Aug 18.
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.
转化生长因子-β（TGF-β）是一种普遍存在的细胞因子，在肿瘤抑制和促进方面具有双重作用，这些双重作用阻碍了针对 TGF-β致癌信号的治疗方法的发展。相比之下，Abl 被很好地确立为造血癌症的启动子；然而，Abl 在调节实体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 TGF-β介导的正常和转移性乳腺上皮细胞（MEC）上皮-间充质转化（EMT）中的作用。在这样做的过程中，我们确定 Abl 是 MEC 形态的重要调节剂，并表明 Abl 失活足以诱导正常 MEC 中的表型和转录 EMT。增加转移性 MEC 中的 Abl 活性导致其完全形态逆转，恢复对 TGF-β的细胞抑制反应，并阻断 TGF-β诱导的基质金属蛋白酶的分泌。组成性激活 Abl 表达可阻断小鼠中 TGF-β 反应性乳腺肿瘤的生长，而伊马替尼治疗在携带乳腺肿瘤的小鼠中没有临床获益。总的来说，这项研究确立了 Abl 作为 MEC 身份的有力调节剂，以及在乳腺肿瘤发生过程中抑制致癌 TGF-β信号的作用。值得注意的是，我们的研究结果强烈警告不要在治疗发育中和进展中的乳腺肿瘤时使用药理学 Abl 拮抗剂。
