Dataset Information

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

ACCESS DATA

Publications

PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression.

Gagliano Teresa T Shah Kalpit K Gargani Sofia S Lao Liyan L Alsaleem Mansour M Chen Jianing J Ntafis Vasileios V Huang Penghan P Ditsiou Angeliki A Vella Viviana V Yadav Kritika K Bienkowska Kamila K Bresciani Giulia G Kang Kai K Li Leping L Carter Philip P Benstead-Hume Graeme G O'Hanlon Timothy T Dean Michael M Pearl Frances Mg FM Lee Soo-Chin SC Rakha Emad A EA Green Andrew R AR Kontoyiannis Dimitris L DL Song Erwei E Stebbing Justin J Giamas Georgios G

The Journal of clinical investigation 20200601 6

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 an ...[more]

PMID: 32125284

Similar Datasets

Project description:BackgroundBreast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC.MethodsThe necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models.ResultsKnockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo.ConclusionsTogether, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.

Dataset Information

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

Publications

PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure