Use of letrozole as a chemopreventive agent in aromatase overexpressing transgenic mice.
Our recent studies have shown that overexpression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in mammary glands, and gynecomastia and testicular cancer in male aromatase transgenic mice. Our studies also have shown that aromatase overexpression-induced changes in mammary glands can be abrogated with very low concentrations of letrozole, an aromatase inhibitor without any effect on normal physiology. In the present study, we have examined the effect of prior low dose letrozole treatment on pregnancy and lactation. We have also investigated the effect of low dose letrozole treatment on subsequent mammary growth and biochemical changes in these animals. There was no change in the litter size, birth weight and no visible birth defects in letrozole-treated animals. Although, there was an insignificant increase in mammary growth in aged animals after 6 weeks of letrozole treatment, the levels of expression of estrogen receptor, progesterone receptor and genes involved in cell cycle and cell proliferation remained low compared to control untreated animals. These observations indicate that aromatase inhibitors such as letrozole can be used as chemopreventive agents without effecting normal physiology in aromatase transgenic mice.
Luthra
Roopa
R
Department of Gynecology and Obstetrics, Emory University School of Medicine, 4217 Woodruff Memorial Building, Atlanta, GA 30322-4710, USA.
Kirma
Nameer
N
Jones
Jeremy
J
Tekmal
Rajeshwar Rao
RR
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D047072:Aromatase Inhibitors; D001724:Birth Weight / Q000187:drug effects; D005260:Female; D006965:Hyperplasia; D007774:Lactation / Q000187:drug effects; D000077289:Letrozole; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D047072:Aromatase Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole; D001141:Aromatase