Int5/Aromatase Effect of Breast Estrogen in Neoplasia

多项研究表明，乳腺肿瘤组织中芳香酶水平高于正常组织，提示原位芳香酶/乳腺雌激素可能在乳腺癌中起一定作用。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，芳香酶的过度表达会导致芳香酶转基因小鼠发生癌前病变(早期乳腺癌)。即使没有循环的卵巢雌激素，这些变化也是持久的。我们还发现：芳香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、肿瘤抑制基因和参与细胞程序性死亡和细胞周期的基因的表达；这些动物在诱发乳腺肿瘤时容易受到致癌物的影响；芳香酶在上皮细胞和基质细胞中都有表达；癌前病变可以在不影响正常生理的情况下被芳香酶抑制剂消除。据我们所知，这是第一个清楚地表明乳腺组织芳香化酶/雌激素直接参与肿瘤发生的活体模型。这些研究的独特性和主要意义在于，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。总的目标是阐明芳香酶过表达对乳腺组织的影响的分子机制，并探讨治疗药物在预防雌激素诱导的乳腺癌前病变中的潜在应用。为此，我们将：1)我们将确定芳香酶转基因小鼠乳腺的致癌潜力；2)我们将研究ERα和βER及PR在没有ERα的情况下，芳香酶过表达诱导的乳腺癌前病变中的作用；3)我们将利用芳香酶x PRKO杂交小鼠，研究PR缺乏对芳香酶过表达诱导的乳腺癌前病变的影响；4)我们将测试A)一种天然的芳香化酶抑制剂，如红酒是否可用作化学预防剂，B)芳香酶抑制剂的化学预防可降低环境致癌物的敏感性，进而可能降低芳香酸酶小鼠乳腺癌的发生。我们目前对癌前病变及其向恶性肿瘤进展的遗传学和生物学方面的知识是不完整的，我们的芳香酶模型将是一个有价值的工具，可以提供新的信息，并有助于了解癌前病变及其进展的生物学。这项研究的结果还将有助于了解乳腺雌激素在乳腺癌的发生和/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.