Int5/Aromatase Effect of Breast Estrogen in Neoplasia

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A number of studies have shown that the levels of aromatase are higher in breast tumors compared to normal tissue, indicating that the in situ aromatase/breast estrogen may play a role in breast cancer. Aromatase catalyzes the conversion of androgens to estrogen, which is the rate- limiting step in estrogen biosynthesis. Our studies have showed that aromatase overexpression resulted in the induction of premalignant lesions (early breast cancer) in aromatase transgenic mice. These changes are persistent even without circulating ovarian estrogens. We have also shown that: aromatase overexpression affects the expression of estrogen receptor (ER) and progesterone receptor (PR), and the expression of various growth factors, oncogenes, tumor suppressor genes and genes involved in programmed cell death and cell cycle; these animals were susceptible to carcinogens in inducing mammary tumors; aromatase is expressed both in epithelial and stromal cells; and preneoplastic changes can be abrogated with aromatase inhibitors without affecting normal physiology. To our knowledge this is the first in vivo model that clearly demonstrated the direct involvement of breast tissue aromatase/estrogen in tumorigenesis. The uniqueness and major significance of the proposed studies is in our use of a novel mouse model to study the role of breast tissue estrogen in normal mammary development, premalignant changes and tumorigenesis. The overall objective is to elucidate the molecular mechanisms that are affected in breast tissue as a result of aromatase overexpression and investigate the potential use of therapeutic agents in prevention of estrogen-induced premalignant breast cancer. To accomplish this: 1) We will determine the tumorigenic potential of mammary glands of aromatase transgenic mice; 2) we will investigate the role of ER alpha and beta, and PR in aromatase overexpression-induced preneoplastic changes in the absence of ERalpha; 3) we will investigate how lack of PR affects the aromatase overexpression-induced preneoplastic changes using aromatase x PRKO cross mice, and 4) we will test whether A) a natural aromatase inhibitor like red wine can be used as a chemopreventive agent and B) the chemoprevention with aromatase inhibitors reduces the susceptibility to environmental carcinogens that may, in turn, reduce the occurrence of breast cancer in aromatase mice. Our current knowledge of the genetics and biology of precancerous lesions and their progression to malignant cancers is incomplete and our aromatase model will be a valuable tool to provide novel information and aid in understanding the biology of precancerous lesions and their progression. The outcome of this study will also help to understand the direct role of mammary estrogen in the initiation and/or promotion of breast cancer and may aid in designing therapeutic approaches for the prevention of estrogen-mediated malignancies.