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Data availability
The RNA sequencing data are available in Gene Expression Omnibus database, with the accession number GSE134615. All other data supporting the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
We thank members of the laboratory of K.-L.G. for discussions. This work was supported by National Cancer Institute grant CA207504 (to J.Z.) and National Institutes of Health grants R01CA217642 and GM51586 (to K.-L.G.).
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Contributions
S.M. and K.-L.G. conceived the study with advice from J.Z., R.L.J. and M.G.R. S.M. performed the majority of the experiments and data analyses with help from Z.W. and F.Y. The manuscript was written by S.M. and K.-L.G., with input from all of the authors.
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K.-L.G. is a cofounder of and has equity interest in Vivace Therapeutics. The other authors declare no competing interests.
Extended data figures and tables
Extended Data Fig. 1 LATS1/2 are required to maintain ERα and target-gene expression.
a, Impaired YAP phosphorylation in LATS1/2 double-knockout cells. Wild-type MCF-7 cells, and two MCF-7 LATS1/2 double-knockout clones, were serum-starved or treated with 1 μM cerivastatin (for 1 h), and subjected to immunoblot analysis. b, Increased YAP and TAZ transcriptional activity in LATS1/2 double-knockout cells. qPCR of the YAP and TAZ target-genes CTGF and CYR61 (also known as CCN1). c, LATS1/2 deficiency inhibits growth of MCF-7 cells. d, YAP signature and oestrogen receptor signature are among the top upregulated and downregulated gene sets, respectively, in LATS1/2 double-knockout cells. Gene enrichment analysis of LATS1/2-deficient (n = 3) and wild-type (n = 3) MCF-7 cells. Circle size represents the relative gene numbers in each set. Red, enriched in LATS1/2-deficient cells; blue, enriched in wild-type cells. e, Opposite effects of LATS1/2 deletion on the YAP signature genes (red) and oestrogen response signature genes (blue) in MCF-7 cells. Significance, false-discovery rate-adjusted P value. Magnitude of difference, fold change. n = 3 independent samples. f, YAP, TAZ and ERα localization and intensity in wild-type or LATS1/2 double-knockout MCF-7 cells. Scale bar, 20 μm. g, h, Redundancy of LATS1/2 in regulating YAP activity and ERα expression. MCF-7 clones with different sgRNA or shRNA targeting LATS1, LATS2 or both were subjected to qPCR analysis for CTGF and ESR1 (g) or immunoblot (h). i–k, Deletion of Lats1/2 reduces ERα in mouse endometrial organoids. Organoids derived from the endometrial tissues of Lats1+/+Lats2+/+ and Lats1fl/flLats2fl/fl mice were infected with Cre-encoding adenovirus and subjected to immunohistochemistry (i), immunoblot (j) and qPCR analysis (k). Scale bar, 100 μm for bright field, 30 μm for immunohistochemistry. l–n, Deletion of Lats1/2 reduces ERα in mouse Fallopian tube organoids. Organoids derived from the Fallopian tube tissues of Lats1+/+Lats2+/+ and Lats1fl/f/Lats2fl/fl mice were infected with Cre-encoding adenovirus and subjected to immunohistochemistry (l), immunoblot (m) and qPCR analysis (n). Scale bar, 200 μm for bright field, 25 μm for immunohistochemistry staining. ***P < 0.001; mean + s.d.. Gel source data are provided in Supplementary Fig 1.
Extended Data Fig. 2 YAP and TAZ mediate Hippo signalling to repress expression of ESR1.
a, Repression of levels of ERα by TAZ. MCF-7 cells transduced with a control vector, or cDNA encoding Flag–TAZ(4SA) or Flag–TAZ(4SA/S51A), were subjected to immunoblot. TAZ(4SA) is a constitutively active mutant with mutation of the four LATS1/2 phosphorylation sites, and TAZ(4SA/S51A) is defective in TEAD binding. b, c, YAP reduces levels of ERα in additional ER+ breast cancer cell lines. T47D (b) and ZR-75-1 (c) cells transduced with a control vector, Flag–YAP(5SA) or Flag–YAP(5SA/S94A) were analysed by immunoblot. d, The TEAD-binding, but not WW, domain of YAP is essential for CTGF induction. e, f, YAP and TAZ have redundant roles in repressing ERα expression. Wild-type, YAP knockout, TAZ knockout or YAP and TAZ double-knockout MCF-7 cells were subjected to immunoblot (e) or qPCR for ESR1 (f). g, YAP and TAZ double knockout increases expression of the ERα target-genes TFF1 and GREB1. h, i, NF2 deficiency decreases ERα expression, YAP phosphorylation and LATS1 phosphorylation, without affecting LATS1 protein. Wild-type, or three independent clones of NF2-null MCF-7 cells were subjected to immunoblot (h) or qPCR (i). ***P < 0.001; mean + s.d., n.s., not significant. Gel source data are provided in Supplementary Fig 1.
Extended Data Fig. 3 Deletion of LATS1/2 inhibits growth of ER+ breast cancer cells.
a, Image representative of six biologically independent xenografts for Fig. 2h. Scale bar, 10 mm. b–d, LATS1/2 deficiency inhibits tumour cell proliferation and promotes apoptosis in vivo. Representative images (b) and analysis (c, d) of ERα, phosphorylated histone H3 (S10) and cleaved caspase 3 immunostaining in LATS1/2-deficient and wild-type MCF-7 xenografts. Scale bar, 100 μm. Box plots indicate median and interquartile range.
Supplementary information
Supplementary Figure 1
This file contains the uncropped western blot source images.
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Ma, S., Wu, Z., Yang, F. et al. Hippo signalling maintains ER expression and ER+ breast cancer growth. Nature 591, E1–E10 (2021). https://doi.org/10.1038/s41586-020-03131-5
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DOI: https://doi.org/10.1038/s41586-020-03131-5
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