mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.
mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.
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DOI：
10.1371/journal.pgen.1005291
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发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
Brantley-Sieders DM
中科院分区：
文献类型：
--
作者：
Morrison MM;Young CD;Wang S;Sobolik T;Sanchez VM;Hicks DJ;Cook RS;Brantley-Sieders DM
Akt磷酸化是发育和疾病中细胞存活、运动和增殖的主要驱动力，引起对Akt样mTOR复合物2（mTORC 2）的上游调节剂的兴趣增加。我们使用Rictor的遗传破坏来损害小鼠乳腺上皮中的mTORC 2活性，其降低Akt磷酸化、导管长度、次级分支、细胞运动性和细胞存活。这些作用在mTORC 1/mTORC 2的药理学双重抑制剂中重现，但在通过Raptor缺失对mTORC 1功能进行遗传破坏后不重现。令人惊讶的是，Akt再激活不足以挽救细胞存活或侵袭，并且适度增加了培养物和体内mTORC 2受损的乳腺上皮细胞（MEC）的分支。然而，另一种mTORC 2底物，蛋白激酶C（PKC）-α，完全拯救mTORC 2受损MEC分支，侵袭和存活，以及体内分支形态发生。PKC-α介导的信号转导通过小GTCRac 1是必要的mTORC 2依赖性乳腺上皮发育在青春期，揭示了一个新的角色Rictor/mTORC 2在MEC的生存和运动在分支形态发生通过PKC-α/Rac 1依赖性机制。蛋白激酶mTOR在乳腺癌中经常被激活，它增强癌细胞的生长、存活和向远处器官的扩散。因此，mTOR是设计用于治疗转移性乳腺癌的药物的有吸引力的、临床相关的分子靶标。然而，mTOR存在于两种不同的复合物中，mTORC 1和mTORC 2，并且每种复合物的相对作用尚未阐明。此外，由于调节正常组织生长和发育的途径经常被劫持以促进癌症，因此了解mTOR在正常乳腺上皮发育中的功能可能会深入了解其在肿瘤进展中的作用。在这项研究中，我们评估了mTORC 1和mTORC 2复合物在正常乳腺上皮细胞分支，存活和侵袭中的作用。有趣的是，虽然mTORC 1不是乳腺上皮细胞分支、存活和侵袭所必需的，但mTORC 2在小鼠和人类模型中对这些过程都是必需的。此外，我们发现mTORC 2主要通过下游激活PKC-α-Rac 1信号轴而不是更充分研究的Akt信号通路发挥其作用。我们的研究确定了mTORC 2复合物在乳腺形态发生中的新作用，包括细胞存活和运动，这与乳腺癌进展有关。
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism. The protein kinase mTOR is frequently activated in breast cancers, where it enhances cancer cell growth, survival, and metastastic spread to distant organs. Thus, mTOR is an attractive, clinically relevant molecular target for drugs designed to treat metastatic breast cancers. However, mTOR exists in two distinct complexes, mTORC1 and mTORC2, and the relative roles of each complex have not been elucidated. Moreover, as pathways that regulate normal tissue growth and development are often highjacked to promote cancer, understanding mTOR function in normal mammary epithelial development will likely provide insight into its role in tumor progression. In this study, we assessed the role of mTORC1 and mTORC2 complexes in normal mammary epithelial cell branching, survival, and invasion. Interestingly, while mTORC1 was not required for branching, survival and invasion of mammary epithelial cells, mTORC2 was necessary for these processes in both mouse and human models. Furthermore, we found that mTORC2 exerts its effects primarily through downstream activation of a PKC-alpha-Rac1 signaling axis rather than the more well-studied Akt signaling pathway. Our studies identify a novel role for the mTORC2 complex in mammary morphogenesis, including cell survival and motility, which are relevant to breast cancer progression.
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影响因子：
11.2
作者：
Janku F;Wheler JJ;Naing A;Falchook GS;Hong DS;Stepanek VM;Fu S;Piha-Paul SA;Lee JJ;Luthra R;Tsimberidou AM;Kurzrock R
通讯作者：
Kurzrock R
STAT5激活和乳腺分化需要AKT。
DOI：
10.1186/bcr2640
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chen CC;Boxer RB;Stairs DB;Portocarrero CP;Horton RH;Alvarez JV;Birnbaum MJ;Chodosh LA
通讯作者：
Chodosh LA
DOI：
10.1158/1541-7786.mcr-07-2203
发表时间：
2008-10
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Cheng N;Chytil A;Shyr Y;Joly A;Moses HL
通讯作者：
Moses HL
用PI3K/AKT/MTOR轴抑制剂治疗的晚期癌症患者的PIK3CA突变。
影响因子：
5.7
作者：
Janku F;Tsimberidou AM;Garrido-Laguna I;Wang X;Luthra R;Hong DS;Naing A;Falchook GS;Moroney JW;Piha-Paul SA;Wheler JJ;Moulder SL;Fu S;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
15.9
作者：
Brantley-Sieders, Dana M.;Zhuang, Guanglei;Chen, Jin
通讯作者：
Chen, Jin