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HDAC inhibitors induce transcriptional activation of Hippo pathway signaling and is associated with improved outcomes in Hormone Receptor positive breast cancer

ABSTRACT: Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Treatment modalities for HR (+) metastatic breast cancer (mBC) includes endocrine therapy (tamoxifen, fulvestrant, aromatase inhibitors) in addition to targeted therapies (CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors, histone deacetylase (HDAC) inhibitors, and others. The hippo pathway LATS1/2-YAP/TAZ-TEAD signaling cascade is a fundamentally important pathway that governs multiple essential biological functions in cell biology and cancer biology. YAP/TAZ are often viewed as pro-tumorogenic, however, recent studies support a role of YAP as a tumor suppressor in HR (+) breast cancer due to its inhibition of estrogen signaling. Few studies have investigated the link between HDAC inhibitors and the Hippo pathway. In our study, we demonstrate that HDAC inhibitors induce transcriptional downregulation of YAP expression, while conversely activating a TEAD mediated transcriptional program with upregulation of many Hippo pathway canonical genes. We further identified 4 genes (CCDC80, GADD45A, F3, TGFB2) that were upregulated by HDAC inhibitors and associated with significantly improved survival in a HR (+) breast cancer cohort. We also correlate in patients samples from a clinical cohort of HR (+) metastatic breast cancer that upregulation of Hippo downstream genes are correlated with improved outcomes. Our study provide a novel mechanistic explanation for the clinical benefit of HDAC inhibitors, while providing further experimental support that Hippo-TEAD transcriptional activation profile is associated with better outcomes in HR (+) breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263971 | GEO | 2025/03/05

REPOSITORIES: GEO

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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

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HDAC inhibitors induce transcriptional activation of Hippo pathway signaling and is associated with improved outcomes in Hormone Receptor positive breast cancer

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