Role of adipocytokines, leptin and adiponectin in breast carcinogenesis

脂肪细胞因子、瘦素和脂联素在乳腺癌发生中的作用

• 批准号: 8476998
• 负责人: Dipali Sharma
• 金额: $ 30.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476998
• 关键词: Adipocytes; Affect; Behavior; Biological; Biological Assay; Biological Markers; Body mass index; Breast; Breast Cancer Cell; Breast Cancer Risk Factor; Cancer Patient; Cancerous; Cell Count; Cell Proliferation; Cells; Characteristics; Chemicals; Clinical; Clinical Data; Coculture Techniques; Cyclin D1; Data; Death Rate; Dominant-Negative Mutation; Endocrine; Epidemic; Estrogens; Exhibits; Growth; High Prevalence; Histopathologic Grade; Human; Image; Immunofluorescence Immunologic; Knockout Mice; Leptin; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Menopausal Status; Migration Assay; Mitotic; Molecular; Monitor; Neoplasm Metastasis; Non obese; Nude Mice; Obesity; Oncogenic; Pathway interactions; Patients; Phosphotransferases; Prevalence; Proliferation Marker; Property; Research; Resistance; Role; S-Phase Fraction; STK11 gene; Sampling; Signal Transduction; Small Interfering RNA; System; Tamoxifen; Transplantation; Tumor Burden; Western Blotting; Woman; abstracting; adiponectin; autocrine; base; breast tumorigenesis; carcinogenesis; electric impedance; gain of function; high risk; hormone therapy; improved; in vivo; inhibitor/antagonist; leptin receptor; lymph nodes; malignant breast neoplasm; migration; mortality; novel; novel strategies; outcome forecast; overexpression; paracrine; pre-clinical; response; treatment response; tumor; tumor growth; tumor progression; tumorigenesis

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.

项目概要/摘要： 近年来，发达国家肥胖症的流行已达到流行病的程度。最近， 一项调查肥胖与乳腺癌死亡率关系的研究发现， 体重指数（BMI）最高的五分之一人群， 最低五分之一的妇女。此外，在BMI最高的五分之一女性中， 肿瘤为ER阴性，具有高S期分数、组织学分级、有丝分裂细胞计数、 增殖标记物和更大的肿瘤尺寸。这些临床观察结果不能仅用较高的 与肥胖有关的雌激素水平。重要的是，与绝经状态无关，肥胖 乳腺癌患者表现出较高的淋巴结转移风险、较大的肿瘤负荷和较高的死亡率 与非肥胖乳腺癌患者相比。因此，理解分子机制， 肥胖对乳腺癌患者预后的不利影响至关重要， 采取新的治疗方法。肥胖通过自分泌和 旁分泌作用由两种主要的脂肪细胞因子，瘦素和脂联素介导。我们最近的研究 研究瘦素的致癌作用揭示：i）瘦素通过Stat3激活诱导增殖，ii） 瘦素诱导侵袭和迁移，和iii）瘦素干扰内分泌治疗。反相 脂联素可降低乳腺癌细胞的侵袭和迁移。脂联素激活AMPK， LKB1依赖的方式，并抑制S6K激活，证明LKB1-AMPK-S6K轴参与。 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。这些数据强烈 提示脂联素拮抗瘦素对乳腺癌细胞的促癌作用。我们 研究工作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。旨在开发新的生物标志物来预测肥胖相关的内分泌 我们将研究脂联素和瘦素信号传导的重要组成部分， 使用自动免疫组织化学分析的人乳腺肿瘤样品。鉴于产品的优良 肥胖在美国的流行，我们的研究有可能显着影响绝大多数乳腺癌患者。 癌症患者通过提高他们的治疗反应和总体生存率来治疗高瘦素水平。