Int5/Aromatase Effect of Breast Estrogen in Neoplasia

多项研究表明，乳腺肿瘤中芳香化酶的水平高于正常组织，提示原位芳香化酶/乳腺雌激素可能在乳腺癌中发挥作用。芳香酶催化雄激素转化为雌激素，这是雌激素生物合成的限速步骤。我们的研究表明芳香酶过表达导致芳香酶转基因小鼠的癌前病变（早期乳腺癌）的诱导。即使没有循环卵巢雌激素，这些变化也会持续存在。我们还表明：芳香化酶过表达影响雌激素受体（ER）和孕激素受体（PR）的表达，以及各种生长因子、癌基因、抑瘤基因和程序性细胞死亡和细胞周期相关基因的表达；这些动物易受致癌物诱发乳腺肿瘤的影响；芳香酶在上皮细胞和基质细胞中均有表达；芳香酶抑制剂可以消除瘤前病变，而不影响正常生理。据我们所知，这是第一个明确证明乳腺组织芳香化酶/雌激素直接参与肿瘤发生的体内模型。本研究的独特性和重要意义在于我们使用了一种新的小鼠模型来研究乳腺组织雌激素在正常乳腺发育、癌前病变和肿瘤发生中的作用。总体目标是阐明芳香化酶过度表达对乳腺组织的影响的分子机制，并研究治疗药物在预防雌激素诱导的癌前乳腺癌中的潜在用途。为此：1)我们将确定芳香化酶转基因小鼠乳腺的致瘤潜力；2)在缺乏ER α的情况下，我们将研究ER α、β和PR在芳香化酶过度表达诱导的肿瘤前变化中的作用；3)我们将利用芳香化酶x PRKO杂交小鼠研究缺乏PR如何影响芳香化酶过表达诱导的肿瘤前变化，4)我们将测试A)天然芳香化酶抑制剂如红酒是否可以作为化学预防剂，B)芳香化酶抑制剂的化学预防是否可以降低对环境致癌物的易感性，从而减少芳香化酶小鼠乳腺癌的发生。我们目前对癌前病变及其发展为恶性癌症的遗传学和生物学的了解是不完整的，我们的芳香化酶模型将是一个有价值的工具，为了解癌前病变及其发展的生物学提供新的信息和帮助。这项研究的结果也将有助于了解乳腺雌激素在乳腺癌发生和/或促进中的直接作用，并可能有助于设计预防雌激素介导的恶性肿瘤的治疗方法。

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.