Osteopontin and Bone Metastasis in Breast Cancer

骨桥蛋白和乳腺癌骨转移

• 批准号: 7087001
• 负责人: TOSHIYUKI YONEDA
• 金额: $ 31.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-17 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087001
• 关键词: X ray; angiogenesis; athymic mouse; autocrine; biological signal transduction; bone neoplasms; breast neoplasms; cell migration; diphosphonate; flow cytometry; gel mobility shift assay; histology; integrins; metalloendopeptidases; metastasis; monoclonal antibody; neoplastic cell; nuclear factor kappa beta; osteogenesis; osteopontin; paracrine; protein quantitation /detection; transfection; western blottings

DESCRIPTION (provided by applicant): Osteopontin (OPN) has been implicated in distant metastasis in breast cancer. Breast cancers with elevated OPN expression show increased metastases and plasma OPN levels are elevated in breast cancer patients with metastases. Breast cancer has a strong predilection for spreading to bone. OPN stimulates osteoclastic bone resorption which is an essential requisite for bone metastases. These results collectively suggest that OPN produced in breast cancer plays a stimulatory role in bone metastases. However, whether OPN contributes specifically to bone metastases or generally to all metastases is unclear. More importantly, the mechanism underlying OPN stimulation of metastases remains to be elucidated. In addition, determination of the regulatory mechanism of OPN production in breast cancer cells in bone is important for better understandings of the pathophysiology of bone metastases. Our hypothesis is "breast cancer-produced OPN promotes bone and non-bone metastases in autocrine/paracrine manner with increased production in bone". To perform the study, we have developed an orthotopic model of mouse breast cancer which produces large amounts of OPN and spreads to bone, lung and liver. Our Specific Aims are: 1.To examine the effects of over expression and inhibition of OPN on bone and non-bone metastases 2.To examine autocrine effects of OPN on breast cancer cells 3.To examine paracrine effects of OPN on osteoclastogenesis and angiogenesis 4.To determine the regulatory mechanism of OPN production in breast cancer cells in bone 5.To examine the effects of bisphosphonates on bone and non-bone metastases in relation to OPN production in breast cancer cells Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Suppression of bone metastases is a major advancement in the management of breast cancer patients. This study will define the mechanism by which breast cancer-produced OPN contributes to thepathogenesis of bone and non-bone metastases. Moreover, the study will also clarify the molecular mechanism of the regulation of OPN production in breast cancer cells in bone. OPN is a potential therapeutic target for bone and also non-bone metastases in breast cancer.

描述（由申请人提供）： 骨桥蛋白（OPN）与乳腺癌中的遥远转移有关。 OPN表达升高的乳腺癌显示转移量增加，血浆OPN水平在转移酶的乳腺癌患者中升高。乳腺癌对扩散到骨骼有很强的偏好。 OPN刺激整骨骨吸收，这是骨转移的必要条件。这些结果共同表明，乳腺癌产生的OPN在骨转移中起刺激作用。但是，OPN是否专门为骨转移或通常对所有转移酶做出贡献尚不清楚。更重要的是，转移刺激的基础机制仍有待阐明。此外，确定骨骼乳腺癌细胞中OPN产生的调节机制对于更好地理解骨转移的病理生理学很重要。我们的假设是“乳腺癌产生的OPN以自分泌/旁分泌方式促进骨骼和非骨转移，而骨骼的产生增加”。为了进行这项研究，我们开发了一种小鼠乳腺癌的原位模型，该模型会产生大量的OPN，并扩散到骨，肺和肝脏。我们的具体目的是： 1.检查OPN过度表达和抑制对骨和非骨转移的影响 2.检查OPN对乳腺癌细胞的自分泌作用 3.检查OPN对破骨细胞生成和血管生成的旁分泌作用 4.确定骨骼乳腺癌细胞中OPN产生的调节机制 5.检查双膦酸盐对乳腺癌细胞中OPN产生的骨骼和非骨转移的影响 骨转移是乳腺癌患者发病率和最终死亡率增加的主要原因之一。抑制骨转移是乳腺癌患者治疗的主要进步。这项研究将定义乳腺癌产生的OPN有助于骨骼和非骨转移的人对医生的机制。此外，该研究还将阐明骨骼乳腺癌细胞中OPN产生的调节的分子机制。 OPN是乳腺癌中骨骼和非骨转移的潜在治疗靶标。