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: 7735608
• 负责人: Dipali Sharma
• 金额: $ 32.16万
• 依托单位: EMORY 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735608
• 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; Hand; 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; Phase; Phosphotransferases; Prevalence; Proliferation Marker; Property; Research; Resistance; Role; STK11 gene; Sampling; Signal Transduction; Small Interfering RNA; System; Tamoxifen; Transplantation; Tumor Burden; Western Blotting; Woman; 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; public health relevance; response; treatment response; tumor; tumor growth; tumor progression; tumorigenesis

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.

描述(申请人提供)：近年来，发达国家肥胖症的流行已达到流行病的程度。最近，一项关于肥胖与乳腺癌死亡率关系的研究发现，体重指数(BMI)最高五分之一的肥胖女性的乳腺癌死亡率是最低五分之一的女性的两倍。此外，在体重指数最高的五分之一的女性中，ER阴性的肿瘤比例增加，具有较高的S期比例、组织学分级、有丝分裂细胞计数、增殖标记物的表达水平以及较大的肿瘤体积。这些临床观察不能仅用与肥胖相关的较高雌激素水平来解释。重要的是，与非肥胖乳腺癌患者相比，肥胖乳腺癌患者与非肥胖乳腺癌患者相比，表现出更高的淋巴转移风险、更大的肿瘤负担和更高的死亡率，这与他们的绝经状态无关。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对于帮助设计适当的新治疗方法至关重要。肥胖通过瘦素和脂联素两种主要脂肪细胞因子介导的自分泌和旁分泌作用影响乳腺癌的发生。我们最近对瘦素的致癌作用的研究表明：1)瘦素通过激活STAT3诱导增殖，2)瘦素诱导侵袭和迁移，3)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LKB1依赖的方式激活AMPK，并抑制S6K的激活，表明LKB1-AMPK-S6K轴参与其中。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转导和生物学效应的分子机制。为了开发新的生物标记物来预测肥胖相关的内分泌抵抗，我们将使用自动化免疫组织化学分析来检测临床注释的人类乳腺肿瘤样本中脂联素和瘦素信号的重要组成部分。考虑到美国肥胖率很高，我们的研究有可能通过改善患者的治疗反应和总体存活率来显著影响绝大多数瘦素水平较高的乳腺癌患者。 公共卫生相关性：该项目将调查一个新的概念，即脂肪细胞因子脂联素拮抗脂肪细胞因子瘦素的致癌作用，从而在乳腺癌的发生中起到保护作用。我们将阐明脂联素和瘦素信号之间的串扰。在此提出的体内研究将确立脂联素作为乳腺癌进展和转移的新的负性调节因子，提供必要的临床前数据。