Abstract
Abstract How tumor cells genetically lose antigenicity and evade intrinsic tumor suppression barriers has been uncertain for decades. Here, we report that tissue-specific expression of a human long noncoding RNA LINK-A in mouse mammary gland initiates metastatic breast tumor, which models human basal-like breast cancer morphologically, genetically, transcriptionally, and metabolically. LINK-A expression facilitates crosstalk between PIP3 and inhibitory GPCRs pathways, leading to decreased cAMP level and protein kinase A (PKA)-mediated phosphorylation of E3 ubiquitin ligase TRIM71. This leads to enhanced K48-polyubiquitination-mediated degradation of tumor suppressor MST1 as well as LATS1. Treatment with LINK-A antisense oligonucleotides or Rauwolscine (a Galphai antagonist) stabilizes Hippo tumor suppressor pathway, sensitizing breast tumors to immune checkpoint blockers. PD-1 blockade-resistant TNBC patients exhibited elevated LINK-A and downregulated Hippo tumor suppressors. We demonstrate an lncRNA-dependent escape from intrinsic tumor suppression and immunosurveillance, which provides a regimen of combinational immunotherapy and effective early prevention for TNBC. Citation Format: Qingsong Hu, Chunru Lin, Liuqing Yang. Oncogenic LncRNA promotes escape from intrinsic Hippo tumor suppression [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA26.
Published Version
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