Renzhi Lin1, Zihan Guan1, QiZhou1, Jijun Zhong2, *, Chenhui Zheng1, Zhuoni Zhang1
1Department of Oncological Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China - 2Department of Nuclear Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China
Objective: 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 difficult to treat. One of the main regulatory factors of TNBC is the construction transcription factor HMGA1. This study aims to further explore the molecular network of HMGA1, a molecular mechanism related to the progression of breast cancer.
Methods: Sequencing of HMGA1-expressed RNA from the MDA-MB-231 cell line and bioinformatics analysis revealed that the HMGA1 molecule can synergistically regulate common genes. The FOXM1 transcription factor was selected for further investigation. The relationship between HMGA1 and FOXM1 was explored with qRT-PCR, co-immunoprecipitation and protein stability analysis. Subsequently, luciferase analysis was used to assess the VEGFA promoter for the transcriptional activity of HMGA1 and FOXM1. The effects on angiogenesis were assessed in vitro, including the ability of the endothelial cells to form tubes in a conditioned medium exposed to MDA-MB-231 cells expressing HMGA1 and FOXM1 and to inject MDA-MB-231 cells.
Result: FOXM1, a novel molecular partner of HMGA1, can regulate a gene network involving multiple breast cancer markers. HMGA1 forms a complex with FOXM1 and stabilizes it in the nucleus, thereby increasing its transcriptional activity against common target genes, including VEGFA, the primary inducer of angiogenesis. Furthermore, we demonstrate that HMGA1 and FOXM1 synergistically drive breast cancer cells to promote tumour angiogenesis in endothelial cells in vitro and in mouse models. In addition, using a dataset of breast cancer patients, we show that HMGA1 expression is a negative prognostic factor for distant metastasis-free survival and relapse-free survival.
Conclusion: This study revealed that FOXM1 is a key interacting factor for HMGA1 and demonstrated that their synergy increases the aggressiveness of breast cancer by promoting tumour angiogenesis. Therefore, jointly targeting HMGA1 and FOXM1 is a treatment option that can prevent angiogenesis in breast cancer.
HMGA1, breast cancer, prognostic value, molecular mechanism.