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Yes-associated protein (YAP), the downstream transducer of the Hippo pathway, is a key regulator of organ size, differentiation and tumorigenesis. To uncover Hippo-independent YAP regulators, we performed a genome-wide CRISPR screen that identifies the transcriptional repressor protein Trichorhinophalangeal Syndrome 1 (TRPS1) as a potent repressor of YAP-dependent transactivation. We show that TRPS1 globally regulates YAP-dependent transcription by binding to a large set of joint genomic sites, mainly enhancers. TRPS1 represses YAP-dependent function by recruiting a spectrum of corepressor complexes to joint sites. Loss of TRPS1 leads to activation of enhancers due to increased H3K27 acetylation and an altered promoter-enhancer interaction landscape. TRPS1 is commonly amplified in breast cancer, which suggests that restrained YAP activity favours tumour growth. High TRPS1 activity is associated with decreased YAP activity and leads to decreased frequency of tumour-infiltrating immune cells. Our study uncovers TRPS1 as an epigenetic regulator of YAP activity in breast cancer.

c-Myc (MYC) is an oncogenic transcription factor that is commonly overexpressed in a wide variety of human tumors. In breast cancer, MYC has recently been linked to the triple-negative subtype, a subtype that lacks any targeted therapy. Previously, we demonstrated that MYC behaves as a potent repressor of YAP and TAZ, 2 transcriptional coactivators that function as downstream transducers of the Hippo pathway. In this previous study, MYC repressed YAP/TAZ not only in primary breast epithelial cells but also in mouse models of triple-negative tumors. Here, we extend our previous bioinformatic and experimental analyses and demonstrate that MYC deregulation in primary breast epithelial cells leads to a robust repression of TEAD transcription factor activity, the transcription factor family mainly responsible for YAP/TAZ recruitment. Surprisingly, we find that MYC and TEAD activity is able to stratify different breast cancer subtypes in large panels of breast cancer patients. Thus, a deep understanding of the MYC-YAP/TAZ circuitry might yield new insights into the establishment and maintenance of specific breast cancer subtypes.