PIK3C δ expression by fibroblasts promotes triple-negative breast cancer progression.

PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression. J Clin Invest. 2020 Mar 03;: 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 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...
Source: Clinical Breast Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Invest Source Type: research