Use of letrozole as a chemopreventive agent in the aromatase overexpression transgenic mouse model

N. Kirma, U. K. Mandava, R. R. Tekmal

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Abstract

Our recent studies have shown that over-expression of aromatase results in increased tissue estrogenic activity and induction of hyperplastic and dysplastic lesions in mammary glands of female mice and gynecomastia and testicular cancer in male aromatase transgenic mice. Previously we have reported that the specific aromatase inhibitor letrozole was effective in completely abrogating the aromatase-induced preneoplastic/neoplastic changes in the mammary gland. However, the chosen dose that is known to reduce tumor growth in xenograft models (5 ug/day) also affected some of the normal endocrinological functions in these animals. In the current study we have investigated using letrozole, whether it was possible to eliminate the estrogen-mediated initiation of breast cancer in the aromatase transgenic mice without affecting normal physiological processes. Our results indicate that the changes induced as a consequence of overexpression of aromatase in the mammary glands can be abrogated with very low concentrations of letrozole. Using low concentrations of letrozole (0.25-0.5 ug/day), it was possible to exert no effect on the normal endocrine physiology as indicated by no significant changes in the circulating levels of estradiol and follicle-stimulating hormone, in addition to exerting no effects on estrogen-responsive genes such as the progesterone receptor and lactoferrin in the uterine tissue. In contrast however, the same concentrations were effective in blocking the estrogen-mediated effects on the mammary gland as assessed histologically. Consistent with decreased mammary cell proliferation, we have also seen decreases in the protein levels of such markers as ER, PR, cyclin D1 and PCNA in the mammary tissues of letrozole-treated animals. The observations indicate that the aromatase inhibitor letrozole, can be used as an effective chemopreventive agent in our transgenic mouse model without effecting the normal endocrine physiology.

Original languageEnglish (US)
Number of pages1
JournalBreast Cancer Research and Treatment
Volume69
Issue number3
StatePublished - Dec 1 2001
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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