Breast Cancer Osteolysis--Regulation of PTHrP by TGFBeta

描述(改编自申请者摘要)：常见乳腺癌 晚期疾病患者骨转移到骨骼 破坏(溶骨性转移)和伴随的疼痛、高钙血症、 骨折和神经卡压综合征。溶骨性骨病的组织学分析 骨转移表明，骨破坏是由 破骨细胞。肿瘤产生的甲状旁腺激素相关蛋白(PTHrP)， 最初被认为是一种高钙因子，也是一种已知的 破骨细胞性骨吸收，是骨溶解过程的主要介体。 转化生长因子(TGF)β，丰富于骨基质中，释放为 破骨细胞性骨吸收的结果，通过以下方式刺激PTHrP的产生 癌细胞。在过去的五年里，由这笔赠款支持的工作 确定了转化生长因子β在促进乳腺癌的恶性肿瘤中的新作用 通过刺激PTHrP的肿瘤产生而起到骨溶解作用。这种观念有悖于 人们普遍认为，转化生长因子β在恶性肿瘤中的主要作用是 肿瘤抑制因子。这一竞争性更新将剖析分子 调控乳腺癌PTHrP产生的机制 TGFBeta。首席调查员实验室的初步数据显示 1)转化生长因子β刺激甲状旁腺素释放的作用是通过以下途径实现的 Smad和丝裂原活化蛋白(MAP)信号通路；2) 一个结构性活性雌激素受体(ER)-α突变(Tyr537Asn)， 从人类骨转移中鉴定，当在人类乳腺癌中表达时 细胞进一步增加转化生长因子β刺激的甲状旁腺素相关蛋白的产生。以下是 具体的假设将被检验：1.TGFf3促进溶骨性骨 乳腺癌通过Smad和MAP激酶信号通路的转移 增加甲状旁腺素受体。2.具有结构性活性的ER-a增加PTHrP的产生和 乳腺癌细胞与肿瘤生长因子b相互作用的溶骨转移 信号通路。3.阻断受体中的TGFb信号通路 能更有效地减少溶骨性骨转移 单独靶向Smad或MAP激酶通路。4.TGFb--响应 PTHrP以外的因素导致乳腺癌骨溶解。以下是 提出了检验假设的具体目标：1)确定 肿瘤生长因子b促进乳腺癌细胞甲状旁腺素释放的机制。2) 确定TGFb的中和是否能有效地阻断骨溶解 转移与中和PTHrP或抑制PTHrP相比如何？ 破骨细胞性骨吸收？3)以确定是否有其他TGFb反应因子， 在溶骨性转移中起作用，如果是这样的话 因素增强甲状旁腺素对骨溶解的影响。拟议的工作将 洞察溶骨性骨转移的机制，这将 导致有效的治疗。

DESCRIPTION (Adapted from the Applicant's Abstract): Breast cancer commonly metastasizes to the skeleton in patients with advanced disease to cause bone destruction (osteolytic metastases) and the associated pain, hypercalcemia, fracture and nerve compression syndromes. Histological analysis of osteolytic bone metastases indicate that the bone destruction is mediated by the osteoclast. Tumor-produced parathyroid hormone-related protein (PTHrP), originally identified as a hypercalcemic factor and a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process. Transforming growth factor (TGF) beta, abundant in bone matrix and released as a consequence of osteoclastic bone resorption, stimulates PTHrP production by cancer cells. Over the past five years, work supported by this grant has identified a new role for TGFbeta in malignancy to promote breast cancer osteolysis by stimulating tumor production of PTHrP. This notion is contrary to the popular belief that the major role of TGF beta in malignancy is that of a tumor suppressor. This competitive renewal will dissect the molecular mechanisms responsible for the regulation of breast cancer PTHrP production by TGFbeta. Preliminary data from the Principal Investigator's laboratory indicate that 1) the effect of TGF beta to stimulate PTHrP production is mediated by both the Smad and mitogen-activated protein (MAP) kinase signaling pathways; 2) A constitutively active estrogen receptor (ER)- alpha mutation (Tyr537Asn), identified from a human bone metastasis, when expressed in human breast cancer cells further increased TGF beta-stimulated production of PTHrP. The following specific hypotheses will be tested: 1. TGFf3 promotes osteolytic bone metastases by breast cancer via both Smad and MAP kinase signaling pathways to increase PTHrP. 2. A constitutively active ER-a increases PTHrP production and osteolytic metastases by breast cancer cells through interaction with the TGFb signaling pathways. 3. Blockade of the TGFb signaling pathway in the receptor level will be a more effective way to decrease osteolytic bone metastases than targeting either the Smad or MAP kinase pathways alone. 4. TGFb-responsive factors other than PTHrP contribute to breast cancer Osteolysis. The following specific aims are proposed to test the hypotheses: 1 )To determine the mechanisms by which TGFb increases PTHrP production by breast cancer cells. 2) To determine if neutralization of TGFb will effectively block osteolytic metastases How does this compare with neutralization of PTHrP or inhibition of steoclastic bone resorption? 3) To determine if other TGFb-responsjye factors, recognized and unrecognized, have a role in osteolytic metastases and if such factors enhance the effects of PTHrP on osteolysis. The proposed work will provide insight into the mechanisms of osteolytic bone metastases which will result in effective therapy.