The LATS2 tumor suppressor, a positive regulator of p53, inhibits hepatic cholesterol accumulation and prevents aggressive luminal B breast cancer

LATS2 is a core kinase of the Hippo tumor suppressor pathway. Previously, we demonstrated that LATS2 possesses functions that go beyond its canonical role in the Hippo pathway, some of which rely on its ability to bind and inhibit MDM2. In this way, LATS2 contributes to p53 activation in response to mitotic and oncogene-driven stress. Furthermore, a positive feedback loop between p53 and LATS2 is activated in response to such stresses. We have generated mice harboring a conditional allele of Lats2. When Lats2 is specifically knocked-out in the liver (Lats2^delHep), mice develop spontaneous fatty liver disease due to their inability to inhibit SREBP. When challenged with excess dietary cholesterol, Lats2^delHep mice manifest more severe liver damage than wild-type mice, in conjunction with attenuated p53 activation, suggesting that LATS2-p53 activation plays a long-term tissue-protective role in this setting. Similarly, mammary gland-specific deletion of Lats2 (Lats2^delMam) in a mouse model for luminal B breast cancer augments tumor burden and aggressiveness. This is in line with analysis of human breast cancer mega-datasets, in which we observe that LATS2 (but not its paralog LATS1) mRNA is specifically downregulated in luminal B breast cancer, and this is positively correlated with elevated risk of relapse.