HMGA1 promotes breast cancer angiogenesis supporting the stability, nuclear localization and transcriptional activity of FOXM1.
Animals
Cell Line, Tumor
Cell Nucleus
/ metabolism
Culture Media, Conditioned
/ pharmacology
Endothelial Cells
/ cytology
Female
Forkhead Box Protein M1
/ chemistry
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Silencing
HEK293 Cells
HMGA1a Protein
/ genetics
Humans
Prognosis
Promoter Regions, Genetic
Protein Stability
Sequence Analysis, RNA
Survival Analysis
Transcription, Genetic
Triple Negative Breast Neoplasms
/ genetics
Vascular Endothelial Growth Factor A
/ genetics
Zebrafish
Angiogenesis
FOXM1
Gene network
HMGA1
Triple-negative breast cancer
VEGFA
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
16 Jul 2019
16 Jul 2019
Historique:
received:
24
05
2019
accepted:
02
07
2019
entrez:
18
7
2019
pubmed:
18
7
2019
medline:
14
1
2020
Statut:
epublish
Résumé
Breast cancer is the most common malignancy in women worldwide. Among the breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive and the most difficult to treat. One of the master regulators in TNBC progression is the architectural transcription factor HMGA1. This study aimed to further explore the HMGA1 molecular network to identify molecular mechanisms involved in TNBC progression. RNA from the MDA-MB-231 cell line, silenced for HMGA1 expression, was sequenced and, with a bioinformatic analysis, molecular partners HMGA1 could cooperate with in regulating common downstream gene networks were identified. Among the putative partners, the FOXM1 transcription factor was selected. The relationship occurring between HMGA1 and FOXM1 was explored by qRT-PCR, co-immunoprecipitation and protein stability assays. Subsequently, the transcriptional activity of HMGA1 and FOXM1 was analysed by luciferase assay on the VEGFA promoter. The impact on angiogenesis was assessed in vitro, evaluating the tube formation ability of endothelial cells exposed to the conditioned medium of MDA-MB-231 cells silenced for HMGA1 and FOXM1 and in vivo injecting MDA-MB-231 cells, silenced for the two factors, in zebrafish larvae. Here, we discover FOXM1 as a novel molecular partner of HMGA1 in regulating a gene network implicated in several breast cancer hallmarks. HMGA1 forms a complex with FOXM1 and stabilizes it in the nucleus, increasing its transcriptional activity on common target genes, among them, VEGFA, the main inducer of angiogenesis. Furthermore, we demonstrate that HMGA1 and FOXM1 synergistically drive breast cancer cells to promote tumor angiogenesis both in vitro in endothelial cells and in vivo in a zebrafish xenograft model. Moreover, using a dataset of breast cancer patients we show that the co-expression of HMGA1, FOXM1 and VEGFA is a negative prognostic factor of distant metastasis-free survival and relapse-free survival. This study reveals FOXM1 as a crucial interactor of HMGA1 and proves that their cooperative action supports breast cancer aggressiveness, by promoting tumor angiogenesis. Therefore, the possibility to target HMGA1/FOXM1 in combination should represent an attractive therapeutic option to counteract breast cancer angiogenesis.
Sections du résumé
BACKGROUND
BACKGROUND
Breast cancer is the most common malignancy in women worldwide. Among the breast cancer subtypes, triple-negative breast cancer (TNBC) is the most aggressive and the most difficult to treat. One of the master regulators in TNBC progression is the architectural transcription factor HMGA1. This study aimed to further explore the HMGA1 molecular network to identify molecular mechanisms involved in TNBC progression.
METHODS
METHODS
RNA from the MDA-MB-231 cell line, silenced for HMGA1 expression, was sequenced and, with a bioinformatic analysis, molecular partners HMGA1 could cooperate with in regulating common downstream gene networks were identified. Among the putative partners, the FOXM1 transcription factor was selected. The relationship occurring between HMGA1 and FOXM1 was explored by qRT-PCR, co-immunoprecipitation and protein stability assays. Subsequently, the transcriptional activity of HMGA1 and FOXM1 was analysed by luciferase assay on the VEGFA promoter. The impact on angiogenesis was assessed in vitro, evaluating the tube formation ability of endothelial cells exposed to the conditioned medium of MDA-MB-231 cells silenced for HMGA1 and FOXM1 and in vivo injecting MDA-MB-231 cells, silenced for the two factors, in zebrafish larvae.
RESULTS
RESULTS
Here, we discover FOXM1 as a novel molecular partner of HMGA1 in regulating a gene network implicated in several breast cancer hallmarks. HMGA1 forms a complex with FOXM1 and stabilizes it in the nucleus, increasing its transcriptional activity on common target genes, among them, VEGFA, the main inducer of angiogenesis. Furthermore, we demonstrate that HMGA1 and FOXM1 synergistically drive breast cancer cells to promote tumor angiogenesis both in vitro in endothelial cells and in vivo in a zebrafish xenograft model. Moreover, using a dataset of breast cancer patients we show that the co-expression of HMGA1, FOXM1 and VEGFA is a negative prognostic factor of distant metastasis-free survival and relapse-free survival.
CONCLUSIONS
CONCLUSIONS
This study reveals FOXM1 as a crucial interactor of HMGA1 and proves that their cooperative action supports breast cancer aggressiveness, by promoting tumor angiogenesis. Therefore, the possibility to target HMGA1/FOXM1 in combination should represent an attractive therapeutic option to counteract breast cancer angiogenesis.
Identifiants
pubmed: 31311575
doi: 10.1186/s13046-019-1307-8
pii: 10.1186/s13046-019-1307-8
pmc: PMC6636010
doi:
Substances chimiques
Culture Media, Conditioned
0
FOXM1 protein, human
0
Forkhead Box Protein M1
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
HMGA1a Protein
124544-67-8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
313Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro (AIRC)
ID : IG18385
Organisme : Regione Autonoma Friuli Venezia Giulia
ID : TNBCneo
Organisme : Regione Autonoma Friuli Venezia Giulia
ID : RiFT
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