β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.
β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.
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DOI：
10.1371/journal.pgen.1003180
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Swain A
中科院分区：
文献类型：
--
作者：
Francis JC;Thomsen MK;Taketo MM;Swain A
前列腺癌是西方世界男性死亡的主要原因，但几乎没有发现导致前列腺癌发生和发展的频繁基因改变。β-连环蛋白在许多发育过程中是必不可少的，并与许多组织的肿瘤发生有关，包括前列腺癌。然而，对人类前列腺癌样本的表达研究并不清楚这种蛋白在这种疾病中所起的作用。我们在胚胎和成人中进行了体内遗传学研究，以扩大我们对β-连环蛋白在正常和肿瘤前列腺中的作用的理解。我们的基因缺失分析表明，前列腺上皮β-catenin是胚胎前列腺生长和分支所必需的，但在正常成人器官中是必不可少的。在发育过程中，β-catenin控制上皮芽中的前体细胞的数量，并调节一个离散的基因网络，包括c-Myc和Nkx3.1。在PTEN缺失的去势抵抗前列腺癌模型中，β-连环蛋白的缺失表明，在这种情况下，它对疾病的进展是可有可无的。通过体内蛋白质稳定的互补过表达实验表明，即使在没有雄激素的情况下，β-连环蛋白也能促进前列腺发育过程中鳞状上皮的形成。β-连环蛋白的过度表达和Pten缺失能够推动浸润性癌和鳞状化生的进展。这些研究表明，β-连环蛋白对前列腺发育是必不可少的，前列腺上皮细胞中这种蛋白高水平的固有特性是驱动鳞状命运分化。此外，他们还表明，在这种疾病的临床相关模型中，β-连环蛋白的过度表达可以促进侵袭性前列腺癌的发生。这些数据提供了关于癌症进展途径的新信息，这些途径导致了人类致命的前列腺癌。前列腺癌是西方世界男性死亡的主要原因，但与这种疾病有关的基因很少。我们已经在前列腺中进行了深入的体内分析，β-Catenin蛋白在胚胎发生的许多过程中都被证明是重要的，并与肿瘤的发生有关。我们的研究表明，β-连环蛋白对前列腺发育是必不可少的，但在正常的成人器官中是必不可少的。对频繁突变的人类前列腺癌抑制基因Pten Lost的小鼠模型的分析表明，在该模型中，即使在去势的条件下，肿瘤的形成也不需要β-连环蛋白。然而，β-Catenin水平的升高与Pten的丢失可以协同促进侵袭性前列腺癌和鳞状化生的进展。这些数据揭示了β-连环蛋白在前列腺癌中的作用，并为如何相互作用驱动人类前列腺癌提供了新的见解。
Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans. Prostate cancer is a major cause of male death in the Western world, but few genes involved in this disease have been identified. We have undertaken an in-depth in vivo analysis in the prostate of the β-Catenin protein, which has been shown to be important in many processes during embryogenesis and has been implicated in tumorigenesis. Our studies demonstrate that β-Catenin is essential for prostate development but is dispensable in the normal adult organ. Analysis of a mouse model of a frequently mutated human prostate tumour suppressor, Pten loss, revealed that β-Catenin is not required for neoplastic formation in this model, even in castrated conditions. However, increased β-Catenin levels can cooperate with Pten loss to promote the progression of aggressive invasive prostate cancer together with squamous metaplasia. These data uncover the role of β-Catenin in the prostate and provide new insights on how pathways interact to drive human prostate cancer.
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DOI：
10.1056/nejmoa1110000
发表时间：
2012-01-12
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
通讯作者：
Cooney KA
影响因子：
8.8
作者：
Morita, N;Uemura, H;Tsumatani, K;Cho, M;Hirao, Y;Okajima, E;Konishi, N;Hiasa, Y
通讯作者：
Hiasa, Y
影响因子：
4.6
作者：
Lin, Yongshun;Liu, Guoqin;Wang, Fen
通讯作者：
Wang, Fen
影响因子：
2.5
作者：
Mehta, Vatsal;Abler, Lisa L.;Keil, Kimberly P.;Schmitz, Christopher T.;Joshi, Pinak S.;Vezina, Chad M.
通讯作者：
Vezina, Chad M.
影响因子：
1.5
作者：
Lesche, R;Groszer, M;Wu, H
通讯作者：
Wu, H