Osteopontin and Bone Metastasis in Breast Cancer

描述（由申请人提供）： 骨桥蛋白（OPN）与乳腺癌的远处转移有关。具有升高的OPN表达的乳腺癌显示增加的转移，并且在具有转移的乳腺癌患者中血浆OPN水平升高。乳腺癌很容易扩散到骨骼。骨桥蛋白刺激骨细胞骨吸收，这是骨转移的必要条件。这些结果共同表明，乳腺癌中产生的OPN在骨转移中起刺激作用。然而，骨桥蛋白是否特异性地促进骨转移或通常促进所有转移尚不清楚。更重要的是，OPN刺激转移的机制仍有待阐明。此外，确定骨中乳腺癌细胞中OPN产生的调节机制对于更好地理解骨转移的病理生理学是重要的。我们的假设是“乳腺癌产生的OPN以自分泌/旁分泌的方式促进骨和非骨转移，并增加骨中的产生”。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，该模型产生大量的OPN并扩散到骨骼、肺和肝脏。我们的具体目标是： 1.研究骨桥蛋白过表达和抑制对骨转移和非骨转移的影响， 2.检测OPN对乳腺癌细胞的自分泌作用 3.研究OPN对破骨细胞生成和血管生成的旁分泌作用。 4.探讨骨组织中乳腺癌细胞OPN表达的调控机制。 5.研究二膦酸盐对乳腺癌细胞骨转移和非骨转移的影响， 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管理的一个重大进步。本研究将明确乳腺癌产生的骨桥蛋白参与骨和非骨转移的发病机制。此外，该研究还将阐明骨中乳腺癌细胞中OPN产生调控的分子机制。骨桥蛋白是乳腺癌骨转移和非骨转移的潜在治疗靶点。

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.