Microarray of primary human breast cells with or without Hippo kinases LATS1/2

Perturbation of the tightly regulated dynamic process of cell fate underlies many human diseases. The molecular mechanisms regulating breast cell fate in the hierarchically organized luminal and basal lineages of breast epithelium remain largely elusive. We performed a high-content confocal image-based shRNA screen for regulators of primary human breast cell fate. Inhibition of the Hippo kinases LATS was found to promote luminal fate and increase the number of progenitors, which is a paradox given that Hippo effectors YAP/TAZ have been associated with basal fate. Mechanistically, LATS loss increases the activities of YAP/TAZ and ER, which in concert control breast cell fate via intrinsic and paracrine effects. Reduced LATS expression is found in breast cancers with a poor prognosis; this diminishes the sensitivity of ER-positive- and increases the sensitivity of ER-negative cancers to endocrine therapy. Thus, in this study we have unraveled crosstalk between Hippo and estrogen signaling and shown that LATS loss triggers expansion of luminal progenitors, the highly suspected cell-of-origin in most breast cancers.

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Britschgi A, Duss S, Kim S, Couto JP, Brinkhaus H, Koren S, De Silva D, Mertz KD, Kaup D, Varga Z, Voshol H, Vissieres A, Leroy C, Roloff T, Stadler MB, Scheel CH, Miraglia LJ, Orth AP, Bonamy GM, Reddy VA, Bentires-Alj M