Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to α-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Furthermore, we divided 4T1 tumors according to the degree of fibrosis and characterized the molecular characteristics of the four regions. Finally, the difference in the signaling pathways and sensitivity to 138 drugs was analyzed in patients with TNBC according to α-SMA expression combined with The Cancer Genome Atlas (TCGA) database. The myogenesis, TGF-β, and Notch signaling pathways were upregulated and the patients with TNBC were significantly differentially sensitive to 25 drugs. The results of in vivo experiments showed that the inhibitory effect of embelin on 4T1 tumors with high α-SMA expression was greater than that on 4TO7 tumors with low α-SMA expression. At the same time, embelin significantly decreased α-SMA and PDGFRA expression in 4T1 tumors compared with the control group. Our findings add to understanding of CAF distribution in the 4T1 tumor microenvironment and its possible role in treating cancer.