The role of annexin A6 in breast cancer metastasis

描述(申请人提供)：乳腺癌扩散至肝脏、肺和骨骼等其他器官，在晚期乳腺癌患者中很常见，仍是乳腺癌死亡的主要原因。几个调节肌动蛋白细胞骨架动力学的因素是转移性疾病的关键决定因素，其中包括钙依赖的膜结合蛋白Annexin家族的成员。其中一种蛋白质--膜联蛋白A6(AnxA6)与膜的相互作用动力学略有不同。它与细胞膜的结合抑制了钙离子的内流和细胞的增殖；最近的一份报告显示，AnxA6缺失的MDA-MB-436浸润性乳腺癌细胞以非锚定的方式生长。这一SC2建议是基于这些观察结果和我们的初步数据，表明AnxA6的表达与乳腺癌的运动/侵袭表型呈正相关，AnxA6表达的缺失可能是肿瘤生长典型的从锚定依赖到锚定非依赖的细胞生长转换的关键步骤。然而，AnxA6影响乳腺癌进展的机制以及我们的体外观察是否可以在体内重现仍是未知的。总体假设是，细胞外钙离子诱导的细胞膜相关的AnxA6通过促进乳腺癌细胞与其他细胞和周围细胞外基质的相互作用，促进浸润性/运动性乳腺癌细胞向远处器官的扩散。这将通过两个特定的目标进行测试：1)评估AnxA6是否对体内移动/侵袭性乳腺癌细胞向远处器官的转移至关重要，2)确定在高钙微环境中侵袭性乳腺癌细胞的建立和生长是否需要AnxA6。拟议的研究不仅将确定AnxA6在乳腺癌转移和肿瘤进展中的作用，还将研究如何利用AnxA6依赖的钙处理机制来评估AnxA6作为预防和/或治疗转移性乳腺癌的治疗靶点。

DESCRIPTION (provided by applicant): The spread of breast cancer to other organs such as the liver, lungs and bone, is frequent in patients with advanced forms of the disease, and still accounts for the majority of deaths from breast cancer. Several factors that modulate actin cytoskeleton dynamics are key determinants of metastatic disease among which are members of the annexin family of Ca2+-dependent membrane binding proteins. One of these proteins, annexin A6 (AnxA6) has been shown to interact with membranes with slightly different kinetics. Its association with the cell membrane inhibits Ca2+ influx and cell proliferation; and a recent report revealed that AnxA6-depleted MDA-MB-436 invasive breast cancer cells grew in anchorage-independent manner. This SC2 proposal is based on these observations and our preliminary data suggesting that AnxA6 expression positively correlates with the motile/invasive phenotype of breast cancer and that loss of AnxA6 expression may be a critical step in the switch from anchorage-dependent to anchorage-independent cell growth that is typical of tumor growth. However, the mechanisms by which AnxA6 influences breast cancer progression and whether our in vitro observations can to be reproduced in vivo remain unknown. The overall hypothesis is that extracellular Ca2+- induced cell membrane-associated AnxA6 promotes the spread of invasive/motile breast cancer cells to distant organs by facilitating their interaction wth other cells and with the surrounding extracellular matrix. This will be tested using two specific aims: 1) to assess whether AnxA6 is essential for the metastasis of motile/invasive breast cancer cells to distant organs in vivo, and 2) to determine whether the establishment and growth of invasive breast cancer cells in high Ca2+ microenvironments require AnxA6. The proposed studies will not only determine the role of AnxA6 in breast cancer metastasis and tumor progression but will also examine how AnxA6-dependent Ca2+ handling mechanisms could be exploited to assess AnxA6 as a therapeutic target for the prevention and/or treatment of metastatic breast cancer.