AUTHOR=Li Zi-Xiong , Chen Jie-Xin , Zheng Ze-Jun , Cai Wang-Jing , Yang Xiong-Bin , Huang Yuan-Yuan , Gong Yao , Xu Feng , Chen Yong-Song , Lin Ling 

TITLE=TGF-β1 promotes human breast cancer angiogenesis and malignant behavior by regulating endothelial-mesenchymal transition

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1051148

DOI=10.3389/fonc.2022.1051148

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Endothelial-mesenchymal transition (EndMT) is an important process of angiogenesis, which plays a significant role in in tumor invasion and metastasis, while its regulatory mechanisms in breast cancer remain to be fully elucidated. We previously demonstrated that tumor-associated macrophages (TAMs) can induce EndMT in endothelial cells by secreting CCL18 through the activation of the TGF-β and Notch signaling pathways in breast cancer. This study was designed to study the role of EndMT in breast cancer angiogenesis and progression in order to explore the underlying mechanism.</p></sec><sec><title>Methods</title><p>Immunohistochemistry (IHC) was used to evaluate the expression of microvascular density (MVD) and EndMT markers in breast cancer. TGF-β1 was used to induce EndMT models of differentiated-endothelial breast cancer stem-like cells (BCSLCs). <italic>In vitro</italic> cell migration, proliferation and matrigel tube-formation assays, as well as <italic>in vivo</italic> nude mouse tumor-bearing model and nude mouse dorsal skinfold window chamber (DSWC) model, were utilized to investigate the effects in order to explore the mechanism of EndMT induced by TGF-β1 on breast cancer progression.</p></sec><sec><title>Results</title><p>In this study, we demonstrated that the EndMT markers were positively associated with MVD indicating unfavorable prognosis of invasive ductal carcinoma (IDC) patients. Functionally, TGF-β1 promoted migration, proliferation and angiogenesis of differentiated-endothelial BCSLCs by inducing EndMT <italic>in vitro</italic> and promoted tumor growth and angiogenesis <italic>in vivo</italic>. Mechanically, we revealed TGF-β1 induced EndMT by activation of TGF-β and Notch signaling pathways with increase of p-Smad2/3 and Notch1 expression. Moreover, we found Snail and Slug were key factors of TGF-β and Notch signaling pathways.</p></sec><sec><title>Conclusion</title><p>Our findings elucidated the mechanism of TGF-β1 in the promotion of angiogenesis and progression by EndMT in breast cancer.</p></sec>