NF-kB Signaling in Osteoclastogenesis and Osteolytic Bone Metastasis

描述（由申请人提供）：本申请的长期目标是了解控制乳腺癌骨转移的分子机制。乳腺癌在晚期患者中经常转移到骨骼。与前列腺癌形成成骨细胞病变不同，乳腺癌骨转移通常导致骨溶解，骨溶解常伴有剧烈疼痛、病理性骨折和高钙血症。尽管优先骨转移的分子机制尚不清楚，但人们认为，由乳腺癌细胞激活的破骨细胞介导骨溶解，而不是乳腺癌细胞本身。破骨细胞在刺激骨髓腔骨转移肿瘤生长中起着启动和关键作用。虽然骨微环境允许循环乳腺癌细胞优先存活和生长，但寻骨乳腺癌细胞可能具有促进破骨细胞形成和激活的内在特性。本应用的中心假设是本构核因子κ B (NF-？B)乳腺癌细胞的活性在溶骨骨转移和破骨细胞发生中起着不可或缺的作用。NF - ?B是一种调节多种基因表达的炎症转录因子，包括促炎细胞因子、趋化因子和细胞粘附分子。通过体外和体内模型系统，我们发现构形NF-？乳腺癌细胞中的B活性通过刺激破骨细胞的发生促进溶骨瘤的生长。在这个应用中，基于我们令人兴奋的初步研究，我们将探索NF-？在乳腺癌细胞中，B被失调并被招募到染色质上，通过生化和遗传方法的结合来刺激靶基因的转录。我们将确定NF-？乳腺癌细胞分泌的趋化因子等b诱导基因刺激破骨细胞形成，从而促进溶骨性骨转移。有趣的是,NF - ?B对于破骨细胞的形成也是必不可少的，并且已发现促炎细胞因子和趋化因子通过激活NF- B来促进破骨细胞的分化。然而，与细胞因子不同的是，我们对趋化因子如何激活NF- B知之甚少。因此，我们还将探讨趋化因子如何触发细胞内信号级联来激活NF-？B促进破骨细胞分化。综上所述，这一应用的结果将为研究溶骨转移和NF-？B，并有助于制定治疗骨转移的新策略。公共卫生相关性：这项应用的长期目标是了解为什么乳腺癌经常扩散到骨骼并导致骨骼破坏。伴有骨转移的晚期乳腺癌患者往往无法治愈，并伴有严重的医学并发症。在这个应用中，我们将从机械和治疗两个方面来解决这个具有挑战性的问题。基于我们最近发现的转录因子核因子- κ B (NF-？B)，我们将检查NF-？乳腺癌细胞中B诱导的趋化因子通过诱导破骨细胞（骨吸收细胞）的形成促进骨转移。我们将探讨NF-？B的活性在乳腺癌细胞中受到调节。本研究的新发现将有助于我们开发通过抑制NF- B治疗骨转移的新策略。

DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand the molecular mechanisms which control breast cancer bone metastasis. Breast cancer frequently metastasizes to bone in patients with advanced diseases. In contrast to prostate cancer which forms osteoblastic lesion, bone metastasis of breast cancer typically leads to osteolysis which is often accompanied with severe pain, pathological fracture, and hypercalcaemia. Although the molecular mechanism underlying the preferential bone metastasis is yet to be elucidated, it is believed that osteoclasts activated by breast cancer cells, but not breast cancer cells themselves, mediate osteolysis. Osteoclasts play an initiating and pivotal role in stimulating bone-metastatic tumor growth in the marrow cavity. While bone microenvironments allow circulating breast cancer cells to preferentially survive and grow, bone-seeking breast cancer cells may have intrinsic properties to promote osteoclast formation and activation. The central hypothesis of this application is that constitutive nuclear factor-kappa B (NF-?B) activities in breast cancer cells play an integral role in osteolytic bone metastasis and osteoclastogenesis. NF-?B is an inflammatory transcription factor which regulates a broad range of gene expression, including pro-inflammatory cytokines, chemokines and cell adhesion molecules. Using in vitro and in vivo model systems, we have found that constitutive NF-?B activities in breast cancer cells promote osteolytic tumor growth by stimulating osteoclastogenesis. In this application, based on our exciting preliminary studies, we will explore how NF-?B is disregulated and recruited to chromatin to stimulate target gene transcription in breast cancer cells using a combination of biochemical and genetic approaches. We will determine whether NF-?B-induced genes such as chemokines secreted by breast cancer cells stimulate osteoclast formation, thereby promoting osteolytic bone metastasis. Intriguingly, NF-?B is also essential for osteoclastogenesis, and pro-inflammatory cytokines and chemokines have been found to promote osteoclast differentiation by activating NF-?B. However, unlike cytokines, little is known about how chemokines activate NF-?B. Therefore, we will also explore how chemokines trigger an intracellular signaling cascade to activate NF-?B to promote osteoclast differentiation. Taken together, the results from this application will provide novel insights into osteolytic bone metastasis and osteoclast activation by NF-?B, and help to develop new strategies for treating skeletal bone metastasis. PUBLIC HEALTH RELEVANCE: The long-objectives of this application are to understand why breast cancer frequently spreads to bone and cause bone destruction. Advanced breast cancer patients with bone metastasis are often incurable and possess severe medical complications. In this application, we will attack this challenging issue from both mechanistic and therapeutic aspects. Based on our recent findings on the promotion of bone metastasis by the transcription factor nuclear factor-kappa B (NF-?B), we will examine whether NF-?B- induced chemokines in breast cancer cells promotes bone metastasis by inducing osteoclast (bone resorbing cells) formation. We will explore how NF-?B activities are regulated in breast cancer cells. New findings from our studies will help us to develop novel strategies for treating bone metastasis by inhibiting NF-?B.