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PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression

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Title: PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression
Authors: Gagliano, T
Shah, K
Gargani, S
Lao, L
Alsaleem, M
Chen, J
Ntafis, V
Huang, P
Ditsiou, A
Vella, V
Yadav, K
Bienkowska, K
Bresciani, G
Kang, K
Li, L
Carter, P
Benstead-Hume, G
O'Hanlon, T
Dean, M
Pearl, FM
Lee, SC
Rakha, EA
Green, AR
Kontoyiannis, DL
Song, E
Stebbing, J
Giamas, G
Item Type: Journal Article
Abstract: As there is growing evidence for the tumor microenvironment's (TME) 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 progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was undetectable in breast cancer cell lines. Genetic and pharmacologic gain- and loss-of functions 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 pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which 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 on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets 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.
Issue Date: 1-Jun-2020
Date of Acceptance: 27-Feb-2020
URI: http://hdl.handle.net/10044/1/78943
DOI: 10.1172/JCI128313
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Start Page: 3188
End Page: 3204
Journal / Book Title: Journal of Clinical Investigation
Volume: 130
Issue: 6
Copyright Statement: © 2020, American Society for Clinical Investigation
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Funder's Grant Number: RDB01 79560
NIHR-RP-011-053
Keywords: Breast cancer
Cell Biology
Oncology
Protein kinases
Signal transduction
Breast cancer
Cell Biology
Oncology
Protein kinases
Signal transduction
11 Medical and Health Sciences
Immunology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2020-03-10
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine