Breast Cancer Cells Induce Stromal Fibroblasts to Secrete ADAMTS1 for Cancer Invasion through an Epigenetic Change

Abstract

Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell-precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable.

Stromal cells in tumor microenvironment and breast cancer

“…CYP19, encoding Cytochrome aromatase p450, is another gene that has been found hypomethylated in breast adipose fibroblasts (BAFs), which induce an increase aromatase levels in the breast [64]. Histone H3K27 also is hypomethylated in breast CAFs, resulting in high level of ADAM metallopeptidase with thrombospondin type 1 motif, (ADAMTS1) in CAFs which correlate to more invasive phenotype [65]. Moreover, loss of histone deacetylase 1(HDAC1) expression induces increased osteopontin (OPN) expression within the stromal compartment of invasive breast cancers, which then activate CAFs to promote tumor growth in vivo.…”

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Serglycin is also synthesized by various stromal cells in tumor microenvironment for instance inflammatory cells, endothelial cells and activated fibroblasts [335, 336]. Serglycin is involved in the secretion of inflammatory mediators by these cells, which contribute to tumorigenesis [335, 336].…”

“…Serglycin is involved in the secretion of inflammatory mediators by these cells, which contribute to tumorigenesis [335, 336]. Serglycin plays crucial roles in the storage and secretion of various proteolytic enzymes in inflammatory cells but also regulates their functions upon secretion and may contribute to tumor progression.…”

Insidious Changes in Stromal Matrix Fuel Cancer Progression

“…Production of ADAMTS-1 by fibroblasts is characteristic of many carcinomas and correlates with enhanced secretion of TGF-β1 and IL-1 β [106]. It was shown recently that fibroblasts in co-culture with breast cancer cells upregulate ADAMTS to promote invasion in an epigenetic mechanism, likely through decreased promoter-associated histone methylation[107]. Matrix metalloendopeptidase (CD10), is also expressed by CAFs, elevated in tumor stroma, and has prognostic value in NSCLC and breast cancer, although its precise role in cancer is still being examined [51, 108–111].…”