HMGA1 promotes breast cancer angiogenesis supporting the stability, nuclear localization and transcriptional activity of FOXM1

Abstract

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 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 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 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1307-8) contains supplementary material, which is available to authorized users.

HMGA Genes and Proteins in Development and Evolution

“…Besides, HMGA1 depletion decreased cell viability in these brain endothelial cells [260]. More recently, HMGA1 was shown to interact with the FOXM1 transcription factor for VEGFA promoter binding, inducing tumor angiogenesis in HUVEC cells and in zebrafish xenografts [261]. Similarly, there are also evidences of HMGA2 being involved in the regulation of pro-angiogenic genes like VEGFA, VEGFC, and FGF-2 [262] and in the angiogenesis occurring in diabetic retinopathy [263] ( Figure 3F).…”

LINC00665 enhances tumorigenicity of endometrial carcinoma by interacting with high mobility group AT-hook 1

“…Studies have shown that the silence of HMGA1 represses cancer developmenyt [27,28]. For example, HMGA1 can promote breast cancer angiogenesis via supporting the transcriptional activity of FOXM1 [29]. HMGA1 exacerbates cervical cancer growth via regulating cell cycle and migration/invasion capacity through targeting miR-221/222 [30].…”

LINC00665 enhances tumorigenicity of endometrial carcinoma by interacting with high mobility group AT-hook 1  

“…Studies have shown that the silence of HMGA1 represses cancer development [30,31]. For example, HMGA1 can promote breast cancer angiogenesis via supporting the transcriptional activity of FOXM1 [32]. HMGA1 exacerbates cervical cancer growth via regulating cell cycle and migration/invasion capacity through targeting miR-221/222 [33].…”