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。骨桥蛋白表达升高的乳腺癌转移增加，转移的乳腺癌患者血浆骨桥蛋白水平升高。乳腺癌有很大的扩散到骨骼的倾向。OPN刺激破骨细胞性骨吸收，而破骨细胞性骨吸收是骨转移所必需的。这些结果共同表明，乳腺癌产生的骨桥蛋白在骨转移中起促进作用。然而，目前尚不清楚骨桥蛋白对骨转移的特异性还是对所有骨转移的普遍作用。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产生骨桥蛋白的调控机制对于更好地理解骨转移的病理生理机制具有重要意义。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，增加骨中的产量”。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。我们的具体目标是： 1.检测骨桥蛋白的过表达和抑制对骨转移和非骨转移的影响 2.检测骨桥蛋白对乳腺癌细胞的自分泌作用 3.观察OPN旁分泌对破骨细胞生成和血管生成的影响 4.确定骨肉瘤细胞骨桥蛋白合成的调控机制 5.研究双膦酸类药物对乳腺癌细胞骨转移和非骨转移的影响及其与骨桥蛋白生成的关系。 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一大进步。这项研究将确定乳腺癌产生的骨桥蛋白在骨转移和非骨转移发病机制中的作用机制。此外，该研究还将阐明骨内乳腺癌细胞OPN产生的调控分子机制。OPN是治疗乳腺癌骨转移和非骨转移的潜在靶点。

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.