INDUCTION OF ESTROGEN INDEPENDENCE OF ZR-75-1 HUMAN BREAST-CANCER CELLS BY EPIGENETIC ALTERATIONS

被引:44
作者
VANAGTHOVEN, T [1 ]
VANAGTHOVEN, TLA [1 ]
DEKKER, A [1 ]
FOEKENS, JA [1 ]
DORSSERS, LCJ [1 ]
机构
[1] DR DANIEL DEN HOED CANC CTR, DIV ENDOCRINE ONCOL, 3008 AE ROTTERDAM, NETHERLANDS
关键词
D O I
10.1210/me.8.11.1474
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Antagonists of steroid hormones are clinically important in the management of breast cancer. However, the duration of response!s limited due to the development of hormone-independent tumors in virtually all cases. In an attempt to obtain insight into the mechanisms underlying antiestrogen resistance, the consequences of epigenetic changes in gene expression were studied in vitro. Estrogen-dependent ZR-75-1 human breast cancer cells were treated with 5-azacytidine, an inhibitor of DNA methylation, and cultured in the absence of estradiol or in the presence of antiestrogens. Estrogen-independent cell colonies developed within 3 weeks at high frequency in 5-azacytidine-treated, cultures (0.7 x 10(-3)), in contrast to control Cultures (less than or equal to 10(-8)). The derived cells (ZR/AZA) were resistant to 4-hydroxy-tamoxifen and ICI 164,384, independent of the selection protocol, but had lost the ability to grow anchorage-independent. Whereas expression of estrogen receptor, progesterone receptor, and pS2 were down-regulated, expression of epidermal growth factor (EGF) receptor and HER2/neu were increased in ZR/AZA cells. In contrast to the stable altered expression patterns of estrogen receptor and EGF receptor, transient keratin 7 expression was observed. Transforming growth factor-alpha mRNA was identified in ZR-75-1 cells and ZR/AZA cells and EGF-like peptides were secreted in the culture medium. Proliferation of ZR/AZA cells could be partially inhibited with an EGF receptor-blocking antibody. Presence of both growth factor receptors and possible ligands suggests the development of an autocrine growth mechanism. Our data show that epigenetic alterations of gene expression result in rapid progression of breast cancer cells to hormone independence.
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页码:1474 / 1483
页数:10
相关论文
共 79 条
[52]   ESTROGEN-RECEPTOR VARIANTS IN CLINICAL BREAST-CANCER [J].
MCGUIRE, WL ;
CHAMNESS, GC ;
FUQUA, SAW .
MOLECULAR ENDOCRINOLOGY, 1991, 5 (11) :1571-1577
[53]  
MCLESKEY SW, 1993, CANCER RES, V53, P2168
[54]   EXON SKIPPING GIVES RISE TO ALTERNATIVELY SPLICED FORMS OF THE ESTROGEN-RECEPTOR IN BREAST-TUMOR CELLS [J].
MIKSICEK, RJ ;
LEI, Y ;
WANG, YL .
BREAST CANCER RESEARCH AND TREATMENT, 1993, 26 (02) :163-174
[55]   THE CATALOG OF HUMAN CYTOKERATINS - PATTERNS OF EXPRESSION IN NORMAL EPITHELIA, TUMORS AND CULTURED-CELLS [J].
MOLL, R ;
FRANKE, WW ;
SCHILLER, DL ;
GEIGER, B ;
KREPLER, R .
CELL, 1982, 31 (01) :11-24
[56]   INVESTIGATION OF THE ORIGIN OF VARIANT, TRUNCATED ESTROGEN RECEPTOR-LIKE MESSENGER-RNAS IDENTIFIED IN SOME HUMAN BREAST-CANCER BIOPSY SAMPLES [J].
MURPHY, LC ;
DOTZLAW, H ;
HAMERTON, J ;
SCHWARZ, J .
BREAST CANCER RESEARCH AND TREATMENT, 1993, 26 (02) :149-161
[57]  
NICHOLSON S, 1989, LANCET, V1, P182
[58]   EPIDERMAL GROWTH-FACTOR RECEPTOR (EGFR) STATUS ASSOCIATED WITH FAILURE OF PRIMARY ENDOCRINE THERAPY IN ELDERLY POSTMENOPAUSAL PATIENTS WITH BREAST-CANCER [J].
NICHOLSON, S ;
HALCROW, P ;
SAINSBURY, JRC ;
ANGUS, B ;
CHAMBERS, P ;
FARNDON, JR ;
HARRIS, AL .
BRITISH JOURNAL OF CANCER, 1988, 58 (06) :810-814
[59]  
OSBORNE MP, 1987, BREAST DISEASES, P1
[60]   ACTION OF PURE ANTIESTROGENS IN INHIBITING ESTROGEN-RECEPTOR ACTION [J].
PARKER, MG .
BREAST CANCER RESEARCH AND TREATMENT, 1993, 26 (02) :131-137