TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties.
Biomarkers, Tumor
Breast Neoplasms
/ genetics
Cell Line
Cell Line, Tumor
Cell Transformation, Neoplastic
/ genetics
Female
Gene Expression
Humans
Immunohistochemistry
Mitogen-Activated Protein Kinases
/ metabolism
Oncogenes
Phosphatidylinositol 3-Kinases
/ metabolism
Receptor, trkA
/ genetics
Signal Transduction
Breast cancer
Metastasis
NTRK1
TrkA
Journal
Breast cancer research and treatment
ISSN: 1573-7217
Titre abrégé: Breast Cancer Res Treat
Pays: Netherlands
ID NLM: 8111104
Informations de publication
Date de publication:
Feb 2020
Feb 2020
Historique:
received:
15
11
2019
accepted:
27
11
2019
pubmed:
12
12
2019
medline:
29
9
2020
entrez:
12
12
2019
Statut:
ppublish
Résumé
TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.
Sections du résumé
BACKGROUND/PURPOSE
OBJECTIVE
TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition.
EXPERIMENTAL DESIGN/METHODS
UNASSIGNED
To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression.
RESULTS
RESULTS
TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells.
CONCLUSIONS
CONCLUSIONS
Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.
Identifiants
pubmed: 31823098
doi: 10.1007/s10549-019-05506-3
pii: 10.1007/s10549-019-05506-3
pmc: PMC7337566
mid: NIHMS1600331
doi:
Substances chimiques
Biomarkers, Tumor
0
NTRK1 protein, human
0
Receptor, trkA
EC 2.7.10.1
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
631-642Subventions
Organisme : NCI NIH HHS
ID : R01 CA194024
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA090625
Pays : United States
Organisme : NIH HHS
ID : CA214494
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008752
Pays : United States
Organisme : Susan G. Komen
ID : SAC170079
Pays : United States
Organisme : NIH HHS
ID : CA194024
Pays : United States
Organisme : Breast Cancer Research Foundation
ID : BCRF-18-122
Organisme : NCI NIH HHS
ID : R01 CA214494
Pays : United States
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