title: 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.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Shiaw-Wei
authors.initials: SW
authors.lastname: Tyan
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Kai-Lin
authors.initials: KL
authors.lastname: Peng
authors.forename: Chun-Chin
authors.initials: CC
authors.lastname: Chen
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Kuo
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.forename: Li-Jung
authors.initials: LJ
authors.lastname: Juan
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D009362:Neoplasm Metastasis / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011509:Proteoglycans; D033921:Vesicular Transport Proteins; C075430:serglycin; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human