Role of adipocytokines, leptin and adiponectin in breast carcinogenesis

项目摘要/摘要： 近年来，发达国家的肥胖率已经达到了流行的程度。最近， 一项调查肥胖与乳腺癌死亡率关系的研究发现， 身体质量指数(BMI)最高五分之一的人死于乳腺癌的比例是 处于最低五分之一的女性。此外，在体重指数最高的五分之一的女性中， 肿瘤为ER阴性，具有较高的S期细胞比例、组织学分级、有丝分裂细胞计数、 增殖标记物，以及更大的肿瘤体积。这些临床观察不能仅用更高的 与肥胖有关的雌激素水平。重要的是，无论她们的更年期状态如何，肥胖 乳腺癌患者具有较高的淋巴结转移风险、较大的肿瘤负担和较高的死亡率。 与非肥胖的乳腺癌患者相比。因此，通过以下方式了解分子机制 哪种肥胖对乳腺癌患者的预后有不利影响是至关重要的，以帮助设计 适当的新方法来治疗他们。肥胖通过自分泌和自分泌影响乳腺癌的发生 瘦素和脂联素两种主要脂肪细胞因子介导的旁分泌作用。我们最近的研究 研究瘦素的致癌作用发现：-i)瘦素通过激活STAT3诱导增殖，ii) 瘦素诱导侵袭和迁移，以及iii)瘦素干扰内分泌治疗。显示对立面 脂联素可以减少乳腺癌细胞的侵袭和迁移。脂联素激活急性心肌梗死大鼠心肌AMPK LKB1依赖的方式，并抑制S6K的激活，表明LKB1-AMPK-S6K轴参与。 最重要的是，脂联素治疗阻断了瘦素信号的一些重要步骤。这些数据强烈地 提示脂联素拮抗瘦素对乳腺癌细胞的促癌作用。我们的 研究的重点是研究脂联素阻碍瘦素的分子机制。 信号和生物效应。旨在开发预测肥胖相关内分泌的新生物标志物 ，我们将研究脂联素和瘦素信号的重要成分在临床注释中的作用 人乳腺肿瘤标本的自动免疫组织化学分析。考虑到最高的 肥胖在美国的流行，我们的研究有可能对绝大多数乳房产生重大影响 通过改善癌症患者的治疗反应和总体生存率来提高瘦素水平。

Project Summary/Abstract: The prevalence of obesity in the developed world has reached epidemic proportions in recent years. Recently, a study examining the relationship of obesity with mortality from breast cancer found that obese women in the highest quintile of body mass index (BMI) have double the death rate from breast cancer when compared with women in the lowest quintile. In addition, in women with BMI in the highest quintile, an increased proportion of tumors were ER negative, had a high S-phase fraction, histologic grade, mitotic cell count, expression levels of proliferation markers, and a larger tumor size. These clinical observations cannot be explained only by higher estrogen levels that are associated with obesity. Importantly, independent of their menopausal status, obese breast cancer patients exhibit a higher risk for lymph node metastasis, larger tumor burden and higher mortality when compared with non-obese breast cancer patients. Thus, understanding the molecular mechanism by which obesity adversely affects the prognosis of breast cancer patients is critical in order to help devise appropriate new approaches to their treatment. Obesity affects breast carcinogenesis by autocrine and paracrine actions mediated by two major adipocytokines, leptin and adiponectin. Our recent studies investigating the oncogenic actions of leptin revealed that - i) leptin induces proliferation via Stat3 activation, ii) leptin induces invasion and migration, and iii) leptin interferes with endocrine treatment. Displaying opposing effects, adiponectin reduces invasion and migration of breast cancer cells. Adiponectin activates AMPK in an LKB1-dependent manner, and inhibits S6K activation demonstrating the involvement of LKB1-AMPK-S6K axis. Most importantly, adiponectin treatment blocks some important steps of leptin signaling. These data strongly suggest that adiponectin antagonizes the cancer-promoting effects of leptin on breast cancer cells. Our research efforts are focused on investigating the molecular mechanism by which adiponectin impedes leptin signaling and biological effects. Aiming to develop novel biomarkers to predict obesity related endocrine resistance, we will examine the important components of adiponectin and leptin signaling in clinically annotated human breast tumor samples using automated immunohistochemical analysis. Considering the high prevalence of obesity in the US, our study has the potential to significantly impact the vast majority of breast cancer patients with high leptin levels by improving their treatment response and overall survival.