The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα

• Published in: Nature (London) Vol. 541; no. 7638; pp. 541 - 545
• Main Authors: Britschgi, Adrian, Duss, Stephan, Kim, Sungeun, Couto, Joana Pinto, Brinkhaus, Heike, Koren, Shany, De Silva, Duvini, Mertz, Kirsten D., Kaup, Daniela, Varga, Zsuzsanna, Voshol, Hans, Vissieres, Alexandra, Leroy, Cedric, Roloff, Tim, Stadler, Michael B., Scheel, Christina H., Miraglia, Loren J., Orth, Anthony P., Bonamy, Ghislain M. C., Reddy, Venkateshwar A., Bentires-Alj, Mohamed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.01.2017
• Subjects: 631/532/2118/2436; 692/699/67/1347; Adaptor Proteins, Signal Transducing - agonists; Adaptor Proteins, Signal Transducing - metabolism; Breast - cytology; Breast - enzymology; Breast - pathology; Carrier Proteins - metabolism; Cell Differentiation; Cell Lineage; Cells, Cultured; Estrogen Receptor alpha - agonists; Estrogen Receptor alpha - metabolism; Female; Genes, Tumor Suppressor; Humanities and Social Sciences; Humans; letter; multidisciplinary; Phosphoproteins - agonists; Phosphoproteins - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Serine-Threonine Kinases - deficiency; Protein Serine-Threonine Kinases - metabolism; Proteolysis; Science; Signal Transduction; Transcription Factors; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases; YAP-Signaling Proteins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20829

Ablation of the large tumour suppressor kinases 1 and 2 promotes a luminal breast cell phenotype through stabilization of oestrogen receptor-α, thereby changing human breast cell fate. Hippo kinases and human breast cell fate To investigate the development of human breast cancer, Mohamed Bentires-Alj and colleagues analyse which type of human breast cells give rise to cancer, and look at how tumour regulators affect the fate of both luminal epithelial and basal myoepithelial progenitors and differentiated cells. They carried out an image-based screen looking for the effects of silencing tumour suppressors. They find that the absence of members of the Hippo signalling pathways stabilizes oestrogen receptor-α signalling components to promote a luminal phenotype and increase the number of progenitors. Cell fate perturbations underlie many human diseases, including breast cancer 1 , 2 . Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors 3 , 4 . Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5 , 6 ), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-α (ERα) signalling. 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 and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.