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（由适用提供）：雌激素受体阳性（ER+）乳腺肿瘤是最常见的乳腺肿瘤，并且比所有其他类型的乳腺癌死亡更多。当在早期阶段检测到ER+乳腺癌，通过阻断受体活性或进化的生物合成的骑马疗法可以很好地管理。但是，患有晚期疾病的患者和在骑马治疗期间中继的患者仍然无法治愈。雌激素（17ß-雌二醇，E2）在ER+肿瘤进展中的作用是自相矛盾的。 E2通过激活ER诱导肿瘤生长。但是，临床数据表明，在绝经后女性中，侵入性ER+乳腺肿瘤更为常见，即E2水平下降。重要的是，几项早期研究表明，ER活性具有保护侵入和转移的保护作用。因此，除了其在调节肿瘤生长中的已知作用外，还需要了解ER的侵袭调节。肌动蛋白重塑在调节入侵中起着核心作用。然而，肌动蛋白重塑的马更塑造尚不清楚。最近，我们确定了一种新型的肌动蛋白细胞骨架重塑过程，该过程通过增加皮质肌动蛋白束来抑制癌细胞侵袭。这些抑制性的皮质肌动蛋白束（以sa疮表示，为简单起见）阻碍了膜突起，这对于侵入性活性至关重要。产生结ab的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和活化的肌球蛋白（P2EM-actin）介导的。 P2EM-ACTIN的抑制会减少结ab，从而提高制动器对突出活性并促进入侵。在我们的初步研究中，我们发现突出取决于Profilin-1，RAC GTPase和ARP2/3（P1RA-ACTIN）介导的另一种肌动蛋白重塑过程，该过程由P2EM-ACTIN拮抗。此外，我们最近的数据表明，ER促进了EVL的转录，EVL是P2EM-ACTIN中聚合的驱动力。基于这些发现，我们假设ER活性通过促进P2EM-ACTIN来抑制侵袭，从而增加结ab并抑制P1RA-ACTIN介导的突起。我们将通过追求以下特定目标（SAS）来检验我们的假设。 SA1是确定因ER活性改变引起的肌动蛋白重塑以及它调节突出和侵袭的机制。我们假设ER通过促进EVL转录抑制侵袭，从而增强P2EM-ACTIN，增加结ab的产生并抑制突出。 SA2是为了确定改变ER活性对P2EM-ACTIN和P1RA-ACTIN之间拮抗作用的影响，以及随之而来的对侵入性行为的影响。我们假设ER抑制通过降低P2EM-ACTIN促进侵袭，从而增强P1RA-肌动蛋白介导的蛋白质。如果成功的话，我们提出的研究将通过建立ER防止侵袭的新机制以及为未来的临床研究奠定基础，该研究将侧重于治疗方式，从而特别受益于患有ER+肿瘤的患者，从而产生重大影响。