Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers

被引:164
作者
Dumont, Nancy
Wilson, Matthew B.
Crawford, Yongping G.
Reynolds, Paul A.
Sigaroudinia, Mahvash
Tlsty, Thea D. [1 ]
机构
[1] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA
基金
美国国家卫生研究院;
关键词
epigenetic remodeling; human mammary epithelial cells; microenvironment; ras;
D O I
10.1073/pnas.0807146105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The active acquisition of epigenetic changes is a poorly understood but important process in development, differentiation, and disease. Our work has shown that repression of the p16/pRb pathway in human epithelial cells, a condition common to stem cells and many tumor cells, induces dynamic epigenetic remodeling resulting in the targeted methylation of a selected group of CpG islands. We hypothesized that cells in this epigenetically plastic state could be programmed by the microenvironment to acquire epigenetic changes associated with tumorigenesis. Here, we describe an in vitro model system where epigenetically plastic cells were placed in an environment that induced epithelial to mesenchymal transition (EMT) and led to a program of acquired de novo DNA methylation at targeted sites. In this model, we found that repression of E-cadherin transcription preceded the subsequent acquisition of methylated CpG sites. Furthermore, the induction of EMT was accompanied by de novo methylation of several other gene promoters, including those of the estrogen receptor and Twist. These data demonstrate that signals from the microenvironment can induce phenotypic and gene expression changes associated with targeted de novo epigenetic alterations important in tumor progression, and that these alterations occur through a deterministic, rather than stochastic, mechanism. Given the dynamic epigenetic reprogramming that occurs in these cells, DNA methylation profiles observed in human tumors may reflect the history of environmental exposures during the genesis of a tumor.
引用
收藏
页码:14867 / 14872
页数:6
相关论文
共 31 条
[1]  
Bànkfalvi A, 1999, HISTOPATHOLOGY, V34, P25
[2]   Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro [J].
Brown, KA ;
Aakre, ME ;
Gorska, AE ;
Price, JO ;
Eltom, SE ;
Pietenpol, JA ;
Moses, HL .
BREAST CANCER RESEARCH, 2004, 6 (03) :R215-R231
[3]   Gene expression signature of fibroblast serum response predicts human cancer progression: Similarities between tumors and wounds [J].
Chang, HY ;
Sneddon, JB ;
Alizadeh, AA ;
Sood, R ;
West, RB ;
Montgomery, K ;
Chi, JT ;
van de Rijn, M ;
Botstein, D ;
Brown, PO .
PLOS BIOLOGY, 2004, 2 (02) :206-214
[4]   Of snail, mice, and women [J].
Davidson, NE ;
Sukumar, S .
CANCER CELL, 2005, 8 (03) :173-174
[5]   The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α [J].
Dhasarathy, Archana ;
Kajita, Masahiro ;
Wade, Paul A. .
MOLECULAR ENDOCRINOLOGY, 2007, 21 (12) :2907-2918
[6]   Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast [J].
Droufakou, S ;
Deshmane, V ;
Roylance, R ;
Hanby, A ;
Tomlinson, I ;
Hart, IR .
INTERNATIONAL JOURNAL OF CANCER, 2001, 92 (03) :404-408
[7]   DNA methylation of RASSF1A, Hin-1, RAR-β, cyclin D2 and twist in in situ and invasive lobular breast carcinoma [J].
Fackler, MJ ;
McVeigh, M ;
Evron, E ;
Garrett, E ;
Mehrotra, J ;
Polyak, K ;
Sukumar, S ;
Argani, P .
INTERNATIONAL JOURNAL OF CANCER, 2003, 107 (06) :970-975
[8]  
Fuchs IB, 2002, ANTICANCER RES, V22, P3415
[9]   The epithelial-mesenchymal transition: new insights in signaling, development, and disease [J].
Lee, JM ;
Dedhar, S ;
Kalluri, R ;
Thompson, EW .
JOURNAL OF CELL BIOLOGY, 2006, 172 (07) :973-981
[10]   Quantitative assessment of promoter hypermethylation during breast cancer development [J].
Lehmann, U ;
Länger, F ;
Feist, H ;
Glöckner, S ;
Hasemeier, B ;
Kreipe, H .
AMERICAN JOURNAL OF PATHOLOGY, 2002, 160 (02) :605-612