Inhibition of breast cancer cell metastases using a connexin43 mimetic peptide

使用 connexin43 模拟肽抑制乳腺癌细胞转移

• 批准号: 10010920
• 负责人: Samy Lamouille
• 金额: $ 39.99万
• 依托单位: ACOMHAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010920
• 关键词: 4T1; Affect; Behavior; Binding; Biochemical; Biological Assay; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer cell line; Breast Carcinoma; Cancer Etiology; Cell Proliferation; Cell membrane; Cells; Cessation of life; Characteristics; Collaborations; Connexin 43; Data; Diagnosis; Disease; Distant; Drug Kinetics; Early Diagnosis; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix Proteins; FOXP3 gene; Fibronectins; Gap Junctions; Goals; Heterogeneity; Human; In Vitro; Incidence; Investigational Drugs; Knowledge; Laboratories; Lead; Legal patent; Letters; Licensing; MDA MB 231; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maximum Tolerated Dose; Mediating; Medical; Mesenchymal; Metastatic breast cancer; Microscopy; Microtubules; Modeling; Molecular Target; Mus; Names; Nature; Neoplasm Metastasis; Patient-Focused Outcomes; Peptides; Population; Primary Neoplasm; Process; Property; Publishing; Recurrence; Reporting; Research; Resolution; Rivers; Role; Signal Transduction; Site; South Carolina; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Transitional Cell Carcinoma; Tumor Cell Invasion; Universities; Woman; Xenograft Model; alpha Tubulin; base; breast cancer progression; cancer cell; cancer subtypes; cancer type; carcinogenesis; cell motility; cytotoxic; efficacy testing; experience; improved; in vitro Assay; in vivo; in vivo Model; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; novel therapeutics; orthotopic breast cancer; outcome forecast; peptidomimetics; prevent; protein protein interaction; screening; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; tumorigenic; uptake

PROJECT SUMMARY Breast cancer is one of the most diagnosed type of cancer and second leading cause of cancer-related death among women in the U.S. Treatment remains challenging due to the heterogeneity and highly dynamic nature of breast tumors. Although early detection through screening has largely contributed to a decline in breast cancer-related mortality, tumor recurrence and metastasis still remain associated with poor prognosis. Once the disease becomes metastatic, the median survival is around 12 to 15 months. But more alarming is the incidence of the triple-negative subtype, the most aggressive type of breast cancer, in the younger population. Increasing evidence identifies the epithelial-mesenchymal transition process as a potential contributor of metastasis in this subtype. In fact, breast carcinoma cells that undergo EMT acquire invasive properties that contribute to the formation of metastases. In addition, EMT results in increased expression of extracellular matrix proteins including fibronectin that enhance tumor invasion, regulate cancer cell proliferation, and limit tumor cell responsiveness to therapies. Therefore, there is an urgent need to identify novel molecular targets in breast cancer-associated EMT, and develop new therapeutics to prevent triple-negative breast cancer progression through metastasis. In our previous published research we observed a loss of connexin43 (Cx43) gap junctions at the plasma membrane concomitantly with an increase in intracellular Cx43 expression during EMT. Despite several studies in the field, the role of Cx43 in breast cancer remains ambiguous with roles in suppressing tumor growth as well as facilitating tumor progression and metastasis. Our preliminary research identifies a tumorigenic role for Cx43 in EMT and triple-negative cancer cells through its interaction with microtubules. Regulating localization and activity of Cx43 is associated with the multiple sites for protein–protein interaction within the Cx43 carboxy-terminus (CT). The Cx43 CT includes a tubulin binding domain and we developed a novel Cx43 mimetic peptide named JM2 (juxtamembrane 2) composed of the Cx43 CT encompassing the microtubule binding sequence. Our goal is to assess the therapeutic effect of JM2 to target triple-negative breast cancer in cell-based assays in vitro and in metastatic breast cancer mouse models in vivo. Our proposed research aims to validate Cx43 as a novel molecular target in triple-negative breast cancer, and use JM2 to disrupt Cx43- microtubule interaction without affecting Cx43 expression, thus regulating Cx43 localization and activity more specifically. This proposal aims to fill a gap in knowledge, whereby no previous studies evaluated the tumorigenic role of Cx43 through interaction with microtubules in breast cancer cells and no efficient targeted therapeutics currently exist that can successfully ablate the metastatic potential of triple-negative breast cancer cells.

项目摘要 乳腺癌是最常见的癌症类型之一，也是癌症相关死亡的第二大原因 在美国女性中，由于异质性和高度动态性，治疗仍然具有挑战性 乳腺肿瘤虽然通过筛查的早期发现在很大程度上有助于乳腺癌的减少， 癌症相关死亡率、肿瘤复发和转移仍然与不良预后相关。一旦 当疾病转移时，中位生存期约为12至15个月。但更令人担忧的是 三阴性亚型，最具侵袭性的乳腺癌类型，在年轻人群中。增加 有证据表明，上皮-间质转化过程是这种肿瘤转移的潜在因素。 亚型事实上，经历EMT的乳腺癌细胞获得了侵袭性特性，这有助于乳腺癌的发生。 形成转移。此外，EMT导致细胞外基质蛋白表达增加 包括增强肿瘤侵袭、调节癌细胞增殖和限制肿瘤细胞增殖的纤连蛋白， 对治疗的反应。因此，迫切需要在乳腺癌中鉴定新的分子靶点， 癌症相关的EMT，并开发新的治疗方法，以防止三阴性乳腺癌的进展 通过转移。在我们之前发表的研究中，我们观察到连接蛋白43（Cx43）间隙连接的丢失， EMT期间细胞膜上的Cx43表达增加。尽管 在该领域的一些研究中，Cx43在乳腺癌中的作用与抑制肿瘤的作用仍然不明确 生长以及促进肿瘤进展和转移。我们的初步研究发现了一种致瘤性 Cx43通过与微管的相互作用在EMT和三阴性癌细胞中的作用。调节 Cx43的定位和活性与细胞内蛋白质-蛋白质相互作用的多个位点相关。 Cx43羧基末端（CT）。Cx43 CT包括微管蛋白结合结构域，我们开发了一种新的Cx43 由包围微管的Cx43 CT组成的名为JM 2（微管膜2）的模拟肽 结合序列我们的目标是评估JM 2靶向三阴性乳腺癌的治疗效果， 体外基于细胞的测定和体内转移性乳腺癌小鼠模型。我们的研究目标 验证Cx43作为三阴性乳腺癌的新分子靶点，并使用JM 2破坏Cx43- 微管相互作用而不影响Cx43表达，从而更多地调节Cx43定位和活性 具体来说这项建议旨在填补知识空白，即以前没有研究评估肿瘤发生的可能性。 Cx43通过与微管相互作用在乳腺癌细胞中的作用，并且没有有效的靶向治疗 目前存在可以成功消除三阴性乳腺癌细胞的转移潜能的方法。