title: The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Britschgi
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duss
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Joana Pinto
authors.initials: JP
authors.lastname: Couto
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Heike
authors.initials: H
authors.lastname: Brinkhaus
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Shany
authors.initials: S
authors.lastname: Koren
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Duvini
authors.initials: D
authors.lastname: De Silva
authors.affiliation: Institute of Pathology Liestal, Cantonal Hospital Baselland, 4410 Liestal, Switzerland.
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
authors.affiliation: Institute of Pathology Liestal, Cantonal Hospital Baselland, 4410 Liestal, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaup
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Varga
authors.affiliation: Novartis Institutes for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Voshol
authors.affiliation: Novartis Institutes for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vissieres
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Novartis Institutes for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Leroy
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Roloff
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Swiss Institute of Bioinformatics, 4058 Basel, Switzerland.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stadler
authors.affiliation: Institute of Stem Cell Research, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Scheel
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Venkateshwar A
authors.initials: VA
authors.lastname: Reddy
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.|Department of Biomedicine, University of Basel, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists / Q000378:metabolism; D001940:Breast / Q000166:cytology* / Q000201:enzymology* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D010750:Phosphoproteins / Q000819:agonists / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D047628:Estrogen Receptor alpha; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex