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PIK3C[delta] expression by fibroblasts promotes triple-negative breast cancer progression
- Source :
- Journal of Clinical Investigation. June, 2020, Vol. 130 Issue 6, p3188, 17 p.
- Publication Year :
- 2020
-
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[delta] (f- PIK3C[delta]) as a key regulator of cancer progression. Although PIK3C[delta] 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[delta] in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3C[delta] confers its protumorigenic effects. Inhibition of f-PIK3C[delta] 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[delta] in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C[delta] 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[delta] inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3C[delta] (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.<br />Introduction Triple-negative breast cancer (TNBC; [ER.sup.-], [PR.sup.-], [HER2.sup.-]) represents a molecularly diverse and highly heterogeneous subtype of breast cancer (BC) (15%-20%) with a poor prognosis and high rates of recurrence [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 6
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.627278079
- Full Text :
- https://doi.org/10.1172/JCI128313.