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: 8942894
• 负责人: Ghassan Mouneimne
• 金额: $ 34.09万
• 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/8942894
• 关键词: Accounting; 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; Menopause; Modality; Molecular; Myosin ATPase; Neoplasm Metastasis; Patients; Play; Postmenopause; Prevention; Process; Published Comment; Randomized Clinical Trials; Regulation; Relapse; Role; Selective Estrogen Receptor Modulators; Staging; Subgroup; Symptoms; Testing; Woman; Women' s Health; Work; actin 2; 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(申请人提供)：雌激素受体阳性(ER+)乳腺肿瘤是最常见的诊断乳腺肿瘤，占乳腺癌死亡人数超过所有其他类型的总和。当在早期阶段被发现时，ER+乳腺癌可以通过激素疗法得到很好的管理，这种疗法可以阻止受体的活性或雌激素的生物合成；然而，晚期疾病患者和在激素治疗期间复发的患者仍然是无法治愈的。雌激素在ER+肿瘤进展中的作用是矛盾的。雌激素通过激活ER诱导肿瘤生长；然而，临床数据表明，侵袭性ER+乳腺肿瘤在绝经后，即E2水平下降后更常见。重要的是，早期的几项研究表明，ER活性具有防止侵袭和转移的保护作用。因此，除了已知的调控肿瘤生长的作用外，有必要了解内质网对侵袭的调控。肌动蛋白重塑在侵袭的调节中起着核心作用；然而，激素对肌动蛋白重塑的调节还不是很清楚。最近，我们发现了一种新的肌动蛋白细胞骨架重塑过程，它通过增加皮质肌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(为了简单起见，这里用结痂表示)阻碍了对侵袭性活动至关重要的膜突起。肌动蛋白重塑过程是由肌动蛋白结合蛋白Profilin-2、肌动蛋白聚合因子EVL和激活的肌球蛋白(P2EM-肌动蛋白)介导的。抑制P2EM-肌动蛋白可减少结痂，从而解除突起活动的刹车，促进侵袭。在我们的初步研究中，我们发现突起依赖于由profilin-1、Rac GTPase和Arp2/3(P1RA-actin)介导的另一种肌动蛋白重塑过程，该过程可被P2EM-肌动蛋白拮抗。此外，我们最新的数据表明，内质网促进了EVL的转录，EVL是P2EM-肌动蛋白聚合的驱动因素。基于这些发现，我们假设ER活性通过促进P2EM-肌动蛋白，从而增加结痂和抑制P1RA-肌动蛋白介导的突起来抑制侵袭。我们将通过追求以下特定目标(SA)来验证我们的假设。SA1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P2EM-肌动蛋白，增加结痂的生成，抑制突起，从而抑制侵袭。SA2是为了确定改变ER活性对P2EM-肌动蛋白和P1RA-肌动蛋白拮抗作用的影响以及由此对侵袭行为的影响。我们假设内质网抑制通过减少P2EM-肌动蛋白从而增强P1RA-肌动蛋白介导的突起来促进侵袭。如果成功，我们拟议的研究将产生重大影响，建立一种ER防止侵袭的新机制，并为未来专注于治疗模式的临床研究奠定基础，这些治疗模式将特别有利于ER+肿瘤患者。