GENISTEIN INDUCES ENDOCRINE-RESISTANCE IN BREAST TUMORS

乳腺癌（BC）是一种与年龄相关的疾病，随着年龄的增长，风险急剧增加，因此大约75%的BC病例发生在绝经后妇女（50岁及以上）。这些癌症中的大多数最初是雌激素（E）依赖性的;然而，乳腺肿瘤通常会随着时间的推移而发展成为E非依赖性或内分泌抵抗性。这一进程是一个复杂的过程，据信分为三个阶段。相当多的研究集中在使用激素替代疗法（HRT）的妇女与E-反应性乳腺癌 大多数肿瘤学家/医生不推荐HRT给这些女性。具有讽刺意味的是，有一个显着的增加，在消费的雌激素类黄酮，往往在高水平，绝经后妇女与BC，因为这些物质被认为是一个“安全的”，天然替代HRT。然而，饮食中雌激素类维生素E对E反应性BC女性的安全性尚未得到充分评估。我们在一个已建立的BC动物模型（无胸腺小鼠MCF-7肿瘤）中的初步结果表明，低饮食剂量的染料木黄酮（GEN）可以促进乳腺肿瘤进展到GEN诱导的E-非依赖性（GIEI）状态。如果这种变化发生在女性，可能会使预后恶化，并限制内分泌治疗的有效性。在我们提出的实验中，我们将更精确地定义导致MCF-7肿瘤中的这种表型变化进展为GIEI肿瘤的饮食GEN暴露的剂量和持续时间。我们还将评估雌马酚的潜在代谢产物雌马酚比其母体大豆黄酮更具雌激素性，从而导致类似的表型变化。在一组单独的实验中，并与项目4合作，我们将评估ER-β在MCF-7细胞中的作用，并确定这些弱雌激素是否优先与ER-β结合并介导ER-β依赖的反式激活，在改变BC进展中发挥作用。我们还将与项目4合作进行机制研究，并利用核心C的资源进行微阵列分析，以分析肿瘤从E依赖性肿瘤进展到GIEI肿瘤时的基因表达变化。总之，我们的研究将确定低饮食剂量的GEN或雌马酚在生理相关的饮食水平可能导致进展为E-非依赖性肿瘤的潜在机制。这些 临床前研究对老年妇女的人类健康具有重要意义，因为患有E依赖性BC的妇女正在食用膳食雌激素，而这些雌激素产品的安全性尚不清楚。

Breast cancer (BC) is an age-associated disease, with risk increasing sharply with age, so that approximately 75% of BC cases occur in postmenopausal women (50 years and older). The majority of these cancers initially are estrogen (E)-dependent; however, breast tumors typically progress over time to become E-independent or endocrine-resistant. This progression is a complex process that is believed to occur in three stages. Considerable research has focused on the use of hormone replacement therapy (HRT) by women with E-responsive breast cancer, and most oncologists/physicians do not recommend HRT to these women. Ironically, there has been a dramatic increase in the consumption of estrogenic isoflavones, often at high levels, by postmenopausal women with BC, because these substances are perceived to be a "safe", natural alternative to HRT. The safety of the dietary estrogenic isoflavones for women with E-responsive BC, however, has not been adequately evaluated. Our preliminary results in an established animal model for BC (MCF-7 tumors in athymic mice) indicate that low dietary doses of genistein (GEN) can facilitate the progression of breast tumors to a GEN-induced E-independent (GIEI) state. If such a change were to occur in women, it might worsen prognosis and limit the effectiveness of endocrine therapy. In our proposed experiments, we will define more precisely the dose and duration of exposure of dietary GEN that causes this phenotypic change in MCF-7 tumors to progress to GIEI tumors. We will also evaluate the potential for the isoflavone metabolite equol, which is more estrogenic than its parent isoflavone daidzein, to cause a similar phenotypic change. In a separate set of experiments and in collaboration with Project 4, we will evaluate the role of ER-beta in MCF-7 cells and determine whether these weak estrogens, which bind preferentially to ER-beta and mediate ER-beta dependent transactivation, play a role in altering BC progression. We will also conduct mechanistic studies in collaboration with Project 4 and using the resources of Core C to conduct microarrays analysis to profile gene expression changes as tumors progress from E-dependent to GIEI tumors. In summary, our studies will determine potential mechanisms by which low dietary dosages of GEN or equol at physiologically relevant dietary levels can cause progression to an E-independent tumor. These preclinical studies have important human health implications in aging women, because women with E-dependent BC are consuming dietary estrogens and the safety of these estrogenic products is unknown.