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: 8134364
• 负责人: Dipali Sharma
• 金额: --
• 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/8134364
• 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.

项目总结/文摘: