PIK3C? 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 PIK3C? (f-PIK3C?) as a key regulator of cancer progression. Although PIK3C? 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-PIK3C? in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3C? confers its protumorigenic effects. Inhibition of f-PIK3C? 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 PIK3C? in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C? 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 PIK3C? inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3C? (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.

SUBMITTER: Gagliano T 

PROVIDER: S-EPMC7260014 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature