The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.
The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.
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DOI：
10.1038/nature20829
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发表时间：
2017-01-26
期刊：
影响因子：
64.8
通讯作者：
Bentires-Alj M
中科院分区：
文献类型：
--
作者：
Britschgi A;Duss S;Kim S;Couto JP;Brinkhaus H;Koren S;De Silva D;Mertz KD;Kaup D;Varga Z;Voshol H;Vissieres A;Leroy C;Roloff T;Stadler MB;Scheel CH;Miraglia LJ;Orth AP;Bonamy GM;Reddy VA;Bentires-Alj M
细胞命运的扰动是许多人类疾病的基础，包括乳腺癌。不幸的是，乳腺细胞命运的调控在很大程度上仍然难以捉摸。乳腺上皮由分化的腔上皮细胞和基底肌上皮细胞以及未分化的干细胞和更有限的祖细胞组成。乳腺癌起源于此上皮，但乳腺上皮分级的分子机制仍然不明确。使用高含量的基于共聚焦图像的shRNA筛选调节乳腺细胞命运的肿瘤抑制因子，我们发现Hippo激酶大肿瘤抑制因子（LATS）1和2的消融促进了管腔表型并增加了双能和管腔祖细胞的数量，这是大多数人类乳腺癌的起源细胞。从机制上讲，我们揭示了Hippo和ERα信号之间的串扰。在LATS存在下，ERα被靶向泛素化和Ddb 1-cullin 4-associated-factor 1（DCAF 1）依赖性蛋白酶体降解。LATS的缺失稳定了ERα和Hippo效应子雅普/TAZ，它们通过内在和旁分泌机制共同控制乳腺细胞的命运。我们的研究结果揭示了一种新的非经典（即，图1显示了LATS在调节人乳腺细胞命运中的作用（不依赖于雅普/TAZ）。
Cell fate perturbations underlie many human diseases, including breast cancer. Unfortunately, the regulation of breast cell fate remains largely elusive. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium but the molecular mechanisms underlying breast epithelial hierarchy remain ill-defined. Using a high-content confocal image-based shRNA screen for tumor suppressors regulating breast cell fate, we have discovered that ablation of the Hippo kinases large tumor suppressors (LATS) 1 and 2, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cell-of-origin of most human breast cancers. Mechanistically, we revealed a crosstalk between Hippo and ERα signaling. In the presence of LATS, ERα was targeted for ubiquitination and Ddb1–cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERα and the Hippo effectors YAP/TAZ, which in concert control breast cell fate via intrinsic and paracrine mechanisms. Our findings reveal a novel non-canonical (i.e., YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
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影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1186/bcr1734
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Duss S;André S;Nicoulaz AL;Fiche M;Bonnefoi H;Brisken C;Iggo RD
通讯作者：
Iggo RD
影响因子：
2.5
作者：
Howard, BA;Gusterson, BA
通讯作者：
Gusterson, BA
影响因子：
8
作者：
Doane, A. S.;Danso, M.;Gerald, W. L.
通讯作者：
Gerald, W. L.
影响因子：
50.3
作者：
Li W;Cooper J;Zhou L;Yang C;Erdjument-Bromage H;Zagzag D;Snuderl M;Ladanyi M;Hanemann CO;Zhou P;Karajannis MA;Giancotti FG
通讯作者：
Giancotti FG