Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer.
Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer.
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DOI：
10.3390/cancers13215343
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发表时间：
2021-10-25
期刊：
影响因子：
5.2
通讯作者：
Jeruss JS
中科院分区：
文献类型：
--
作者：
Decker JT;Ma JA;Shea LD;Jeruss JS
抑制细胞周期蛋白依赖性激酶（CDK）的小分子在治疗乳腺癌方面具有很大的潜力，并已在一些转移性疾病患者的标准治疗中实施。随着CDK抑制剂的适应症不断扩大，了解这些药物的作用机制以及与其他靶向治疗的相互作用至关重要。因此，本综述讨论了亚型特异性系统性乳腺癌治疗，通过转化生长因子β（TGFβ）信号传导的影响，以及CDK抑制剂治疗的独特潜力。TGFβ信号传导通过促进几种细胞调节作用（包括细胞周期控制和凋亡）在正常细胞中产生肿瘤抑制功能。典型的TGFβ信号传导通过转录因子SMAD 3在蛋白质C末端的磷酸化进行。在致癌进展期间，SMAD 3的这种肿瘤抑制剂磷酸化可以被抑制。在乳腺癌中经常观察到细胞周期蛋白D和E的过表达以及随后的细胞周期蛋白依赖性激酶2/4（CDK）的过度活化，并且与不良预后相关。CDK 2和4对SMAD 3的非典型磷酸化导致SMAD 3的肿瘤抑制功能受到抑制。因此，CDK过度活化驱动致癌进展，并且可以靶向改善临床结果。本文综述了乳腺癌，并强调了CDK介导的非经典SMAD 3磷酸化的理解进展。具体而言，将检查异常TGFβ信号传导在致癌进展和治疗反应中的作用，以说明在细胞周期蛋白/CDK和SMAD 3背景下的治疗发现潜力。
Small molecules that inhibit cyclin dependent kinases (CDKs) have great potential for the treatment of breast cancer and have been implemented in the standard of care for some patients with metastatic disease. As the indications for CDK inhibitors continue to expand, and it is crucial to understand the mechanism of action of these drugs and treatment interactions with other targeted therapies. Accordingly, this review discusses subtype-specific systemic breast cancer treatment, the effects of signaling through transforming growth factor beta (TGFβ), and the unique potential for implementation of CDK inhibitor therapy. TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3.
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影响因子：
2.5
作者：
Flanders KC;Wakefield LM
通讯作者：
Wakefield LM
影响因子：
4.3
作者：
Dean, Jeffry L.;McClendon, A. Kathleen;Knudsen, Erik S.
通讯作者：
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DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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