PZR在乳腺癌进展和转移中机理和功能的研究

Most of the breast cancer patients will die eventually due to metastasis and recurrence of the diseases after developing resistance to therapies. One of the mechanisms that contribute to breast cancer recurrences is that breast cancer stem cells (BCSC)，which are usually quiescent。 No currently available drugs are effective in preventing the spread of breast cancer to other tissues and killing BCSC. Identifying molecules and understand how they drive the metastasis of breast cancer and controls BCSC pool should provide targets for future drug development specifically in preventing metastasis and overcoming recurrence of breast cancer. In this grant, we propose to study the novel function of PZR (protein-zero related), a cell surface transmembrane protein, in breast cancer. Specifically, we hypothesize that the high level of PZR protein expression plays a critical role in driving the aggressive growth phenotypes of breast cancer, which are shared by ER negative and triple negative breast cancer (TNBC). We will examine whether PZR regulates the extracellular matrix (ECM)-cell signaling pathway to promote the growth, migration, and invasion, epithelial to mesenchymal transition, maintenance of BCSC of breast cancer cells in vitro and in vivo. We will also provide proof-of-concept that targeting PZR is effective in inhibiting the metastatic growth of BC in mouse models. In addition, we will examine whether PZR can be used as a novel breast cancer biomarker for tumor stage, breast cancer subtypes and metastasis by examining PZR expression in primary human breast tumor samples. The results of our study will demonstrate that targeting PZR and PZR regulated pathway are potential novel therapies to treat metastatic breast cancer especially TNBC effectively.

乳腺癌是妇女最常见的恶性肿瘤之一，大多数乳腺癌患者最终死于转移和对疗法产生抗药性后的疾病复发。乳腺癌干细胞(BCSC)是乳腺癌复发的机制之一。目前尚无有效药物防止乳腺癌扩散和转移。BCSC通常被认为对目前疗法不敏感。这项研究中，我们发现了细胞表面跨膜蛋白PZR在乳腺癌转移中的新功能。试验显示PZR在ER（-）和三阴性乳腺癌（TNBC）中高表达，接下来的实验证实PZR可以促进乳腺癌细胞生长、迁移、侵袭、上皮间质转化（EMT）和BCSC数量的维持，将用异种移植小鼠模型进行体内试验验证并进一步通过体内体外实验验证PZR是否通过调节细胞外基质（ECM）细胞信号转导通路而发挥此功能。此外我们将验证 PZR可否作为一种新的乳腺癌生物标志物来确定乳腺癌分期、分型、和转移。PZR和PZR所调控的信号通路的研究将可能为转移性乳腺癌特别是TNBC的治疗提供新的药物靶标。

乳腺癌是妇女最常见的恶性肿瘤之一，三阴性乳腺癌是恶性程度高和预后最差的一个乳腺癌亚型并且缺乏靶向疗法。绝大多数乳腺癌患者最终死于转移，乳腺癌干细胞(BCSC)是乳腺癌复发的机制之一，前尚无有效药物防止乳腺癌扩散和转移。 本项研究通过检测细胞表面跨膜蛋白PZR在206例乳腺癌肿瘤样本中的表达，发现PZR在雌激素受体（ER）阴性（P<0.005）和三阴性乳腺癌（TNBC）（P<0.029）肿瘤样本中有高表达，并且PZR高表的乳腺癌病人生存期低 （P<0.041）。在乳腺癌细胞株水平上的研究揭示PZR表达促进乳腺癌细胞的上皮间质转换（EMT）和BCSC 的扩增，异种移植乳腺癌动物模型实验显示PZR表达促进TNBC肿瘤的生长和转移。进一步分子机理研究结果展示PZR通过调控粘着蛋白激酶FAK的激活以及转录共激活因子TAZ的蛋白水平来促进三阴性乳腺癌的侵袭和转移。我们的研究显示PZR是三阴性乳腺癌的潜在生物标志物，揭示了三阴性乳腺癌发病的新的分子机理，并且表明PZR 和PZR 所调控的信号通路将可能为转移性乳腺癌特别是三阴性乳腺癌的治疗提供新的药物靶点。