Microarray of MCF10A cells with/without LATS1/2, expressing YAP/TAZ or ESR1 cDNA

Cell fate perturbations underlie many human diseases, including breast cancer. However, the regulation of breast cell fate remains largely elusive. 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 underlying breast epithelial hierarchy remain ill-defined. Mouse and human luminal cells express keratins (K)18, 8, 19 and/or estrogen receptor α (ERα) and progesterone receptor (PR), their basal counterparts express K5, 14 and/or p63 and/or α-smooth-muscle actin (α-SMA)4-6. In this study, using a high-content confocal image-based shRNA screen for tumor suppressors regulating human breast cell fate, we discovered that ablation of the Hippo kinases large tumor suppressor (LATS) 1 and 2, promoted luminal fate and increased the number of bipotent and luminal progenitors, the proposed cell-of-origin of most human breast cancers. Mechanistically, we discovered a crosstalk between Hippo and ERα signaling. In the presence of LATS, ERα was targeted for ubiquitination and proteasomal degradation. Loss of LATS stabilized ERα and Hippo effectors YAP/TAZ, which in concert control breast cell fate via intrinsic and paracrine mechanisms. Our findings uncover a novel non-canonical (i.e., YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate. In this dataset, we provide microarray gene expression analysis of normal breast epithelial cells, freshly dissociated from reduction mammoplasties, in which LATS1/2 were knocked down comparing it to non-targeting control expressing breast cells. 18 samples were analyzed, 3 replicates. MCF10A cells in which LATS1/2 were knocked down by two different shRNAs (shLATS1B = LATS1 knockdown, shLATS1+2 = LATS1 and LATS2 double knockdown), cells expressing a non-targeting shRNA were used as controls (shNT). Each of these three cell lines was transfected with either a ctrl, YAP/TAZ and/or ESR1 cDNA expressing vector.