Role of adipocytokines, leptin and adiponectin in breast carcinogenesis

描述（由申请人提供）：近年来，发达国家的肥胖症患病率已达到流行病的比例。最近，一项研究调查了肥胖与乳腺癌死亡率的关系，发现体重指数（BMI）最高五分之一的肥胖妇女与体重指数最低五分之一的妇女相比，乳腺癌死亡率高出一倍。此外，在BMI最高的五分位数的女性中，ER阴性的肿瘤比例增加，具有高S期分数，组织学分级，有丝分裂细胞计数，增殖标记物表达水平和较大的肿瘤大小。这些临床观察结果不能仅用与肥胖相关的较高雌激素水平来解释。重要的是，与绝经状态无关，与非肥胖乳腺癌患者相比，肥胖乳腺癌患者表现出更高的淋巴结转移风险、更大的肿瘤负荷和更高的死亡率。因此，了解肥胖对乳腺癌患者预后产生不利影响的分子机制是至关重要的，以帮助设计适当的新方法来治疗乳腺癌。肥胖通过两种主要的脂肪细胞因子瘦素和脂联素介导的自分泌和旁分泌作用影响乳腺癌的发生。我们最近研究瘦素的致癌作用的研究表明，- i）瘦素通过Stat 3激活诱导增殖，ii）瘦素诱导侵袭和迁移，iii）瘦素干扰内分泌治疗。脂联素具有相反的作用，可减少乳腺癌细胞的侵袭和迁移。脂联素以LKB 1依赖的方式激活AMPK，并抑制S6 K激活，表明LKB 1-AMPK-S6 K轴参与其中。最重要的是，脂联素治疗阻断了瘦素信号传导的一些重要步骤。这些数据有力地表明，脂联素拮抗瘦素对乳腺癌细胞的促癌作用。我们的研究工作集中在研究脂联素阻碍瘦素信号传导的分子机制和生物学效应。为了开发新的生物标志物来预测肥胖相关的内分泌抵抗，我们将使用自动免疫组织化学分析来检查临床注释的人类乳腺肿瘤样本中脂联素和瘦素信号传导的重要组分。考虑到肥胖在美国的高患病率，我们的研究有可能通过改善治疗反应和总生存率来显著影响绝大多数瘦素水平高的乳腺癌患者。 公共卫生相关性：本研究将探讨一个新的概念，即脂肪细胞因子脂联素拮抗脂肪细胞因子瘦素的促癌作用，从而在乳腺癌发生中具有保护作用。我们将阐明脂联素和瘦素信号之间的串扰。本文提出的体内研究将建立脂联素作为乳腺癌进展和转移的一种新的负调节因子，提供必要的临床前数据。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project will investigate a novel concept that adipocytokine adiponectin antagonizes the pro-cancerous effects of adipocytokine leptin and hence have a protective role in breast carcinogenesis. We will elucidate the crosstalk between adiponectin and leptin signaling. In vivo studies proposed here will establish adiponectin as a novel negative regulator of breast cancer progression and metastasis providing the necessary pre-clinical data.