Aromatase overexpression and breast hyperplasia, an in vivo model -: continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands

被引:54
作者
Tekmal, RR
Kirma, N
Gill, K
Fowler, K
机构
[1] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30322 USA
[2] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA
关键词
D O I
10.1677/erc.0.0060307
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. Continued overexpression of aromatase that leads to increased breast-tissue estrogen contributes to a number of epigenetic changes in mammary tissue such as alteration in the regulation of genes involved in apoptosis, activation of genes involved in cell cycle and cell proliferation, and activation of a number of growth factors. Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.
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页码:307 / 314
页数:8
相关论文
共 27 条
[1]  
Brodie A, 1997, J STEROID BIOCHEM, V61, P281
[2]  
Brodie A, 1998, ONCOLOGY-NY, V12, P36
[3]   Aromatase inhibitors in advanced breast cancer: Mechanism of action and clinical implications [J].
Brodie, AMH ;
Njar, VCO .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1998, 66 (1-2) :1-10
[4]   AROMATASE AND ITS INHIBITORS IN BREAST-CANCER-TREATMENT - OVERVIEW AND PERSPECTIVE [J].
BRODIE, AMH ;
SANTEN, RJ .
BREAST CANCER RESEARCH AND TREATMENT, 1994, 30 (01) :1-6
[5]   Distribution of aromatase P450 transcripts and adipose fibroblasts in the human breast [J].
Bulun, SE ;
Sharda, G ;
Rink, J ;
Sharma, S ;
Simpson, ER .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1996, 81 (03) :1273-1277
[6]  
Chen SA, 1998, FRONT BIOSCI-LANDMRK, V3, P922
[7]  
CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P156, DOI 10.1016/0003-2697(87)90021-2
[8]   PROGNOSTIC-SIGNIFICANCE OF AROMATASE AND ESTRONE SULFATASE ENZYMES IN HUMAN BREAST-CANCER [J].
EVANS, TRJ ;
ROWLANDS, MG ;
SILVA, MC ;
LAW, M ;
COOMBES, RC .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1993, 44 (4-6) :583-587
[9]  
Gill K., 1998, Proceedings of the American Association for Cancer Research Annual Meeting, V39, P551
[10]   TISSUE-SPECIFIC EXPRESSION OF THE HUMAN AROMATASE CYTOCHROME-P-450 GENE BY ALTERNATIVE USE OF MULTIPLE EXONS-1 AND PROMOTERS, AND SWITCHING OF TISSUE-SPECIFIC EXONS-1 IN CARCINOGENESIS [J].
HARADA, N ;
UTSUMI, T ;
TAKAGI, Y .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (23) :11312-11316