The role of annexin A6 in breast cancer metastasis

膜联蛋白A6在乳腺癌转移中的作用

• 批准号: 8214014
• 负责人: Amos Malle Sakwe
• 金额: $ 14.57万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214014
• 关键词: Accounting; Actins; Adherens Junction; Affect; Anchorage-Independent Growth; Annexin A6; Annexins; BALB/c Nude Mouse; Binding Proteins; Breast Cancer Cell; Calcium; Cardiac; Cell Adhesion; Cell Proliferation; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Characteristics; Cytoskeleton; Data; Disease; Distant; Epidermal Growth Factor Receptor; Estrogens; Extracellular Matrix; Extravasation; Family; Fatty acid glycerol esters; Female; Focal Adhesions; Gene Expression; Goals; Growth; Human; Hypercalcemia of Malignancy; Imaging Techniques; In Vitro; Injection of therapeutic agent; Invaded; Kinetics; Lead; Lesion; Liver; Lung; Mammary gland; Membrane; Metastatic Lesion; Modeling; Molecular Profiling; Neoplasm Metastasis; Organ; Patients; Phenotype; Phospholipids; Prevention; Prevention strategy; Progesterone; Progesterone Receptors; Protein Binding; Proteins; Reporting; Resistance; Role; S-Phase Fraction; Serum; Site; Surface; Tail; Testing; Therapeutic; Time; Veins; base; bone; cancer cell; career; cell growth; cell motility; effective therapy; extracellular; in vivo; malignant breast neoplasm; matrigel; member; neoplastic cell; parathyroid hormone-related protein; prognostic; receptor; research study; therapeutic target; tumor; tumor growth; tumor progression; two-photon; uptake

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. PUBLIC HEALTH RELEVANCE: Cancer metastases are resistant to conventional therapeutics. Therefore a better understanding of how metastases occur should lead to more effective treatments. This project focuses on annexin A6, a protein that binds to the cell surface and influences both calcium uptake and tumor cell growth. The proposed experiments will not only determine the role of annexin A6 in the invasion and establishment of breast cancer cells in the lungs and bone but will also determine whether annexin A6- dependent actions can be validated as a therapeutic strategy for the prevention and/or treatment of metastatic breast cancer.

描述（由申请人提供）：在患有晚期疾病的患者中，乳腺癌传播给肝脏，肺和骨骼等其他器官，但仍然占乳腺癌的大部分死亡。调节肌动蛋白细胞骨架动力学的几个因素是转移性疾病的关键决定因素，其中是Ca2+依赖性膜结合蛋白的膜联蛋白家族的成员。这些蛋白质之一是膜联蛋白A6（AnxA6）已显示与动力学略有不同的膜相互作用。它与细胞膜的关联抑制Ca2+流入和细胞增殖。最近的一份报告表明，止动的MDA-MB-436侵入性乳腺癌细胞以锚固无关的方式生长。该SC2提案基于这些观察结果，我们的初步数据表明，AnxA6表达与乳腺癌的运动/侵入性表型呈正相关，而AnxA6表达的丧失可能是从锚定锚定到锚固依赖性细胞生长的转变的关键步骤，这是肿瘤生长的典型生长。然而，焦虑6的机制影响乳腺癌的进展以及我们的体外观察是否可以在体内再现，这仍然未知。总体假设是细胞外Ca2+ - 诱导的细胞膜相关的ANXA6通过促进其他细胞的相互作用以及与周围细胞外基质的相互作用，促进了侵袭性/运动性乳腺癌细胞向远处的器官的传播。这将使用两个具体目的对此进行测试：1）评估AnxA6对于在体内对运动/侵入性乳腺癌细胞转移对远处器官的转移以及2）确定高CA2+微环境中侵入性乳腺癌细胞的建立和生长是否需要Anka6是否至关重要。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，而且还将研究如何利用AnxA6依赖性CA2+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标。 公共卫生相关性：癌症转移对常规疗法具有抗性。因此，更好地了解转移的发生应导致更有效的治疗。该项目的重点是与细胞表面结合并影响钙摄取和肿瘤细胞生长的蛋白质ANCENXIN A6。提出的实验不仅将确定膜联蛋白A6在肺和骨骼中乳腺癌细胞的侵袭和建立中的作用，而且还将确定是否可以将膜联蛋白A6依赖性作用作为预防和/或治疗转移性乳腺癌的治疗策略验证。