INT-5/AROMATASE--EFFECT OF BREAST ESTROGEN IN NEOPLASIA

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We recently showed that the cellular gene at the mouse mammary tumor virus integration site in the int-5 locus is identical to the gene encoding aromatase (referred as int-5/aromatase). Aromatase catalyzes the conversion of androgens to estrogens. Aromatase levels are higher in breast tumors compared to normal tissue, indicating that the in situ aromatase/breast estrogen may play a role in breast cancer. No studies have demonstrated to direct involvement of mammary aromatasein mammary tumorigenesis. We have developed the int-5/aromaatase transgenic mice model, and demonstrated for the first time that increased mammary estrogenic activity due to the overexpression of int-5/aromatase in female mammary glands leads to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer, that may, in turn, increase the risk of developing aggressive breast cancer. In male transgenic mice, overexpression of int- t/aromatase leads to increased mammary growth and hyperplastic and dysplastic changes that are similar to gynecomastia (early male breast cancer). These observations indicate that increased mammary estrogen alone without the influence of circulating estrogen may be sufficient to induce early breast cancer. Using int-5/aromatase in vivo model we will: 1) examine the effect of increased mammary estrogen on the regulation of oncogenes, growth factors, and tumor suppressor genes implicated in breast cancer as will as genes involved in programmed cell death; 2) determine whether the synergistic interaction of estrogen (int-5/aromatase overexpression) with c-myc or TGFalpha or p53 (plus/minus, minus/minus) in transgenic crosses results in the acceleration and/or increase in the incidence of breast cancer, 3) investigate whether exposing int- 5/aromatase transgenic animals to carcinogens leads to an acceleration and/or increase in the incidence of breast cancer, and 4) determine whether blocking mammary estrogenic activity by therapeutic interventions in early stages of mammary development results in the prevention of preneoplastic/neoplastic changes that may, in turn, reduce the occurrence of breast cancer. The outcome of this study will help to understand the direct role of breast estrogen in the initiation and/or promotion of breast cancer, increased susceptibility to environmental carcinogens and may aid in designing therapeutic approaches for the prevention of estrogen- mediated breast cancer.