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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.).
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
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. Source data
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. Source data
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. Source data
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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