Breast Cancer Osteolysis--Regulation of PTHrP by TGFBeta

描述（改编自申请人的摘要）：乳腺癌通常 在晚期疾病患者中转移到骨骼， 破坏（溶骨性转移）和相关疼痛，高钙血症， 骨折和神经压迫综合征。溶骨性组织学分析 骨转移表明骨破坏是由 破骨细胞肿瘤产生的甲状旁腺相关蛋白（PTHrP）， 最初被鉴定为高钙因子和已知的 骨吸收是溶骨性过程的主要介质。 转化生长因子（TGF）β，在骨基质中丰富， 骨吸收的结果，刺激PTHrP的生产， 癌细胞在过去的五年里，这项赠款支持的工作 发现了TGF β在恶性肿瘤中促进乳腺癌的新作用 通过刺激肿瘤产生PTHrP导致骨质溶解。这一观点与 普遍认为TGF β在恶性肿瘤中的主要作用是 肿瘤抑制因子这种竞争性的更新将剖析分子 负责调节乳腺癌PTHrP生产的机制， TGF β主要研究者实验室的初步数据表明 1）TGF β刺激PTHrP产生的作用由以下介导： Smad和丝裂原活化蛋白（MAP）激酶信号通路; 2） 组成型活性雌激素受体（ER）-α突变（Tyr 537 Asn）， 当在人乳腺癌中表达时， 细胞进一步增加了TGF β刺激的PTHrP的产生。以下 具体的假设将被测试：1。TGF β 3促进溶骨性骨 乳腺癌转移通过Smad和MAP激酶信号通路， 升高PTHrP。2.组成型活性ER-α增加PTHrP产生， 乳腺癌细胞通过与TGF β相互作用的溶骨性转移 信号通路3.受体中TGF β信号通路的阻断 水平将是一种更有效的方式来减少溶骨性骨转移比 单独靶向Smad或MAP激酶途径。4. TGFb反应性 PTHrP以外的其他因素导致乳腺癌骨质溶解。以下 提出了检验假设的具体目标：1）确定 TGF β增加乳腺癌细胞PTHrP产生的机制。（二） 为了确定TGF β的中和是否会有效地阻断溶骨性 这与PTHrP的中和或PTHrP的抑制相比如何？ 骨质疏松性骨吸收？3)为了确定其他TGF β-应答因子， 已知和未识别的，在溶骨性转移中起作用， 因子增强PTHrP对骨溶解的作用。拟议的工作将 提供了对溶骨性骨转移机制的深入了解， 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.