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.

Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry

“…It is worthy noting that the associations between the WWC1 and LATS2 genes and breast cancer risk were mainly found in ER+ participants. There might be synergistic effects between WWC 1, LATS2 , and estrogen receptor . The positive synergistic effects between these genes and ER might provide an uncommon opportunity to detect a larger association, whereas it would be challenging to detect a relatively small association attributing only to genes without the interaction with ER.…”

Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer

“…The three subpopulations of mammary cells obtained are typically referred to as basal cells (BCs), luminal progenitors (LPs), and luminal cells (LCs). Other antibody cocktails have also been used to obtain highly overlapping phenotypes with very similar biological and molecular properties (Raouf et al, ; Bachelard‐Cascales et al, ; Keller et al, ; Kannan et al, ; Nguyen et al, ; Fridriksdottir et al, ; Lawson et al, ; Britschgi et al, ), and additional markers have proven useful to subdivide these three subpopulations of human mammary cells even further (Eirew et al, ; Shehata et al, ; Knapp et al, ; Morel et al, ). However, the combination of antibodies to CD49f and EpCAM has generally been the most widely utilized.…”

“…WNT pathway components also show differential patterns of expression, with biological evidence of their importance in maintaining a mammary stem cell state, at least as inferred from studies of the mouse mammary gland (Teulière et al, ; Roarty & Rosen, ; Zeng & Nusse, ; van Amerongen et al, ; Gu et al, ) with more limited, but consistent data for human cells (Arendt et al, ). Other pathways similarly implicated are the TGF‐β (Moses & Barcellos‐Hoff, ; Kahata et al, ) and the Hippo pathways (Chen et al, ; Pelissier et al, ; Skibinski et al, ; Shi et al, ; Britschgi et al, ). Importantly, all of these are variably deregulated in breast cancers (Howard & Ashworth, ).…”

Cancer: a new role for non-canonical Hippo signaling

“…Notably, LATS1 is cytoplasmic in luminal cells, which may prevent it from facilitating ERα degradation. Britschgi et al [5] speculate that cytosolic LATS can suppress YAP/ TAZ activity in luminal cells, although previous findings have indicated that LATS1/2 are predominantly active in the nucleus [7]. Further work is needed to fully understand in which subcellular compartment LATS1/2 are activated and target YAP in mammary stem cells and their progeny.…”

“…Complex cell fate mechanisms, including differentiation from a stem cell or transdifferentiation from basal cells, may produce luminal progenitors. Britschgi et al [5] found that the Hippo pathway kinases LATS1/2 tightly regulate the fate of primary human breast epithelial stem cells (PHBECs) grown ex vivo. In addition to restraining YAP activation, which drives stem cell self-renewal, LATS1/2 facilitate ERα ubiquitylation by the E3 ligase CRL4 DCAF1 , thereby suppressing luminal progenitor specification and differentiation.…”