{"doi":"10.1172/jci128313","title":"PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression","abstract":"As there is growing evidence for the tumor microenvironment's role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple-negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of cancer progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was barely detectable in breast cancer (BC) cell lines. Genetic and pharmacological gain- and loss-of-function experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its protumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, that led to upregulation of NR4A1 in TNBC cells, where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease in tumor metastasis, emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.","journal":"Journal of Clinical Investigation","year":2020,"id":66053,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":350162,"name":"Kalpit Shah","orcid":"0000-0001-6383-4625","position":1,"is_corresponding":false},{"id":350163,"name":"Sofia Gargani","orcid":"0000-0002-4280-0933","position":2,"is_corresponding":false},{"id":350164,"name":"Liyan Lao","orcid":"0000-0002-1043-9952","position":3,"is_corresponding":false},{"id":350165,"name":"Mansour Alsaleem","orcid":"0000-0002-7689-2493","position":4,"is_corresponding":false},{"id":350166,"name":"Jianing Chen","orcid":"0000-0002-2938-4402","position":5,"is_corresponding":false},{"id":350167,"name":"Vasileios Ntafis","orcid":"0000-0003-1271-1187","position":6,"is_corresponding":false},{"id":350168,"name":"Penghan Huang","orcid":"0000-0002-4921-657X","position":7,"is_corresponding":false},{"id":350169,"name":"Angeliki Ditsiou","orcid":"0000-0003-3743-8447","position":8,"is_corresponding":false},{"id":350170,"name":"Viviana Vella","orcid":"0000-0003-1000-3443","position":9,"is_corresponding":false},{"id":350171,"name":"Kritika Yadav","orcid":"0000-0003-0896-195X","position":10,"is_corresponding":false},{"id":350172,"name":"Kamila Bienkowska","orcid":"0000-0003-4940-1895","position":11,"is_corresponding":false},{"id":352028,"name":"Giulia Bresciani","orcid":null,"position":12,"is_corresponding":false},{"id":267568,"name":"Kai Kang","orcid":"0000-0002-4348-3941","position":13,"is_corresponding":false},{"id":63127,"name":"Leping Li","orcid":"0000-0003-4208-0259","position":14,"is_corresponding":false},{"id":352029,"name":"Philip Carter","orcid":null,"position":15,"is_corresponding":false},{"id":350173,"name":"Graeme Benstead-Hume","orcid":"0000-0003-1478-3985","position":16,"is_corresponding":false},{"id":350174,"name":"Timothy O’Hanlon","orcid":"0000-0003-2759-733X","position":17,"is_corresponding":false},{"id":291441,"name":"Michael Dean","orcid":"0000-0003-2234-0631","position":18,"is_corresponding":false},{"id":350175,"name":"Frances M. 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