Novel Mechanism of Breast Cancer Invasion Prevention by Estrogen Receptor

雌激素受体预防乳腺癌侵袭的新机制

• 批准号: 9379103
• 负责人: Ghassan Mouneimne
• 金额: $ 6.09万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379103
• 关键词: ANGPTL2 gene; Actin-Binding Protein; Actins; Actomyosin; Anabolism; Architecture; Aromatase Inhibitors; Behavior; Breast Cancer Cell; Cause of Death; Cessation of life; Characteristics; Clinical; Clinical Data; Clinical Research; Complex; Cytoskeleton; Data; Diagnosis; Disease; Epidemiology; Estradiol; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exhibits; Future; Gases; Generations; Genetic Transcription; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Hormone replacement therapy; Hormones; Incidence; Laboratories; Lifting; Light; Mammary Neoplasms; Mediating; Membrane; Menopausal Symptom; Modality; Molecular; Myosin ATPase; Neoplasm Metastasis; Patients; Play; Postmenopause; Prevention; Process; Published Comment; Randomized Clinical Trials; Regulation; Relapse; Role; Selective Estrogen Receptor Modulators; Subgroup; Testing; Woman; Women' s Health; Work; advanced disease; base; cancer cell; deprivation; hormone regulation; hormone therapy; malignant breast neoplasm; mortality; neoplastic cell; novel; polymerization; prevent; profilin; profilin 1; protective effect; public health relevance; receptor; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): Estrogen receptor positive (ER+) breast tumors are the most commonly diagnosed tumors of the breast and account for more breast cancer deaths than all other types combined. When detected in its early stages, ER+ breast cancer is well managed with hormone therapies that block the activity of the receptor or the biosynthesis of estrogens; however, patients with advanced disease and those who relapse during hormone therapy remain incurable. The role of estrogen (17ß-estradiol, E2), in ER+ tumor progression is paradoxical. E2 induces tumor growth by activating ER; however, clinical data show that invasive ER+ breast tumors are more common in women post menopause, i.e. after E2 levels have declined. Importantly, several early studies suggest that ER activity has a protective role against invasion and metastasis. Therefore, there is a need to understand ER regulation of invasion apart from its known role in regulating tumor growth. Actin remodeling plays a central role in the regulation of invasion; however, hormone regulation of actin remodeling is not well understood. Recently, we identified a novel actin cytoskeletal remodeling process that suppresses cancer cell invasion by increasing cortical actomyosin bundles. These Suppressive Cortical Actin Bundles (herein denoted by SCABs, for simplicity) impede membrane protrusions, which are crucial for invasive activity. This actin remodeling process that generates SCABs is mediated by the actin binding protein Profilin-2, the actin-polymerization factor, EVL, and activated Myosin (P2EM-actin). Suppression of P2EM-actin decreases SCABs, thus lifting the brakes on protrusive activity and promoting invasion. In our preliminary studies, we found that protrusion is dependent on another actin remodeling process mediated by Profilin-1, Rac GTPase and Arp2/3 (P1RA-actin), which is antagonized by P2EM-actin. Moreover, our most recent data demonstrate that ER promotes the transcription of EVL, the driver of polymerization in P2EM-actin. Based on these findings, we hypothesize that ER activity suppresses invasion by promoting P2EM-actin, thus increasing SCABs and suppressing P1RA-actin mediated protrusions. We will test our hypothesis by pursuing the following specific aims (SAs). SA1 is to determine the actin remodeling caused by altering ER activity and the mechanism by which it modulates protrusion and invasion. We hypothesize that ER inhibits invasion by promoting EVL transcription, thus enhancing P2EM-actin, increasing the generation of SCABs and suppressing protrusion. SA2 is to identify the effects of altering ER activity on the antagonism between P2EM-actin and P1RA-actin and the consequent effects on invasive behavior. We hypothesize that ER suppression promotes invasion by decreasing P2EM-actin thus enhancing P1RA-actin mediated protrusions. If successful, our proposed studies will have a significant impact by establishing a novel mechanism by which ER prevents invasion, and by laying the groundwork for future clinical studies focused on treatment modalities that would particularly benefit patient afflicted with ER+ tumors.

 描述（由申请人提供）：雌激素受体阳性（ER+）乳腺肿瘤是最常诊断的乳腺肿瘤，其乳腺癌死亡人数超过所有其他类型的总和。当在早期阶段检测到ER+乳腺癌时，可以通过阻断受体活性或雌激素生物合成的激素疗法进行良好管理;然而，晚期疾病患者和激素治疗期间复发的患者仍然无法治愈。雌激素（17 β-雌二醇，E2）在ER+肿瘤进展中的作用是矛盾的。E2通过激活ER诱导肿瘤生长;然而，临床数据显示侵袭性ER+乳腺肿瘤在绝经后女性中更常见，即E2水平下降后。重要的是，一些早期的研究表明，ER活性对侵袭和转移具有保护作用。因此，有必要了解ER调节侵袭除了其已知的作用，在调节肿瘤生长。肌动蛋白重构在侵袭的调节中起着核心作用;然而，激素对肌动蛋白重构的调节还不清楚。最近，我们发现了一种新的肌动蛋白细胞骨架重塑过程，通过增加皮质肌动球蛋白束来抑制癌细胞的侵袭。这些抑制性皮质肌动蛋白束（为简单起见，本文中表示为SCAB）阻碍膜突起，这对于侵入活动至关重要。这种产生SCAB的肌动蛋白重塑过程由肌动蛋白结合蛋白Profilin-2、肌动蛋白聚合因子EVL和活化的肌球蛋白（P2 EM-肌动蛋白）介导。P2 EM-肌动蛋白的抑制减少了SCAB，从而解除了对细胞增殖活动的抑制并促进了入侵。在我们的初步研究中，我们发现突起依赖于另一个肌动蛋白重塑过程，该过程由Profilin-1、Rac GT3和Arp 2/3（P1 RA-肌动蛋白）介导，P2 EM-肌动蛋白拮抗该过程。此外，我们最近的数据表明，ER促进EVL的转录，在P2 EM-肌动蛋白聚合的驱动程序。基于这些发现，我们假设ER活性通过促进P2 EM-肌动蛋白抑制侵袭，从而增加SCAB并抑制P1 RA-肌动蛋白介导的突起。我们将通过追求以下特定目标（SA）来测试我们的假设。SA 1是为了确定由改变ER活性引起的肌动蛋白重塑及其调节突起和侵袭的机制。我们推测ER通过促进EVL转录，从而增强P2 EM-肌动蛋白，增加SCAB的产生并抑制突起来抑制侵袭。SA 2是为了确定改变ER活性对P2 EM-肌动蛋白和P1 RA-肌动蛋白之间的拮抗作用的影响以及对侵袭行为的后续影响。我们推测ER抑制通过减少P2 EM-肌动蛋白从而增强P1 RA-肌动蛋白介导的突起来促进侵袭。如果成功，我们提出的研究将通过建立一种新的机制来产生重大影响，通过这种机制ER可以防止入侵，并为未来的临床研究奠定基础，这些临床研究的重点是治疗方式，特别是对患有ER+肿瘤的患者有益。