Aromatase overexpression transgenic mice model: cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology.
Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in female mammary glands and gynecomastia and testicular cancer in male aromatase transgenic mice. Both aromatase mRNA and protein are overexpressed in transgenic mammary glands and its expression is not limited to epithelial cells. However, it is more in epithelial than in stromal cells. Our results also indicate aromatase overexpression-induced changes in mammary glands can be abrogated with very low concentrations of the aromatase inhibitor, letrozole. Low concentration of letrozole had no effect on normal physiology as indicated by no significant change in the circulating levels of estradiol and follicle stimulating hormone as well as no change in estrogen responsive genes such as the progesterone receptor and lactoferrin in the uterine tissue. These observations indicate that the expression of aromatase in both epithelial and stromal cells can influence the complex interactions of biochemical pathways leading to mammary carcinogenesis and that the aromatase inhibitor, letrozole can be used as chemopreventive agents without affecting normal physiology.
Mandava
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Department of Gynecology and Obstetrics, Emory University, 4217 Woodruff Memorial Building, 1639 Pierce Drive, Atlanta, GA 30322-4710, USA.
Kirma
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N
Tekmal
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D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000502:physiology*; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression; D006965:Hyperplasia; D000077289:Letrozole; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology; D014018:Tissue Distribution; D014230:Triazoles / Q000494:pharmacology
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; D004958:Estradiol; D000077289:Letrozole; D005640:Follicle Stimulating Hormone; D001141:Aromatase