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Nature. 2017 Jan 26;541(7638):541-545. doi: 10.1038/nature20829. Epub 2017 Jan 9.

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

Author information

1
Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
2
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
3
Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
4
Institute of Pathology Liestal, Cantonal Hospital Baselland, 4410 Liestal, Switzerland.
5
Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
6
Novartis Institutes for Biomedical Research, 4058 Basel, Switzerland.
7
Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.
8
Institute of Stem Cell Research, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

Abstract

Cell fate perturbations underlie many human diseases, including breast cancer. 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. 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.

PMID:
28068668
DOI:
10.1038/nature20829
[Indexed for MEDLINE]

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