Molecular determinants of breast cancer malignancy

乳腺癌恶性肿瘤的分子决定因素

• 批准号: 8261842
• 负责人: Lalita A. Shevde
• 金额: $ 30.81万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261842
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Apoptotic; Area; Behavior; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cell Proliferation; Cells; Complement; Contact Inhibition; Coupled; Ependymoma; Epithelial Cells; Equilibrium; Event; Foundations; Functional RNA; GLI gene; Glioma; Growth; Human; Invaded; Knowledge; Laboratories; Lead; Loss of Heterozygosity; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modality; Modification; Molecular; Mutation; Neoplasm Metastasis; Nervous System Neoplasms; Nervous system structure; Neurilemmoma; Neurofibromin 2; Non-Malignant; Oncogene Proteins; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Physiological; Play; Post-Transcriptional Regulation; Property; Proteasome Inhibitor; Proteins; Recombinants; Regulation; Reporting; Repression; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Specimen; Testing; Therapeutic Intervention; Transcriptional Regulation; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Ubiquitination; Yin-Yang; base; cancer cell; cell behavior; cell growth; interest; kinase inhibitor; malignant breast neoplasm; meningioma; neoplastic cell; novel; osteopontin; promoter; public health relevance; restoration; small hairpin RNA; tumor; tumor progression

DESCRIPTION (provided by applicant): The oncoprotein, osteopontin (OPN) expressed by tumor cells potentiates their malignant properties, specifically by affecting their ability to grow, invade, and metastasize. Our research shows that OPN downregulates the protein levels of the tumor suppressor protein, Merlin, likely by targeting it for degradation in breast cancer cells. Merlin is a tumor suppressor gene that has been well characterized in various tumor types of the nervous system. In nervous system tumors, Merlin mediates contact inhibition, invasion, cell growth and also impedes proliferation. Recent evidence also implicates that Merlin protein gets degraded rapidly in the above tumor types following post-translation modifications, including Akt-mediated phosphorylation followed by ubiquitination. Merlin is understudied in breast cancer. Interestingly, we also discovered that Merlin exerts a negative regulatory effect on OPN. Based on these findings, we hypothesize that Merlin and OPN reciprocally regulate each other. A balance between the levels of the two proteins is critical to the maintenance of non-malignant cell behavior. Merlin keeps OPN levels under check in untransformed cells. During the pathogenesis of breast cancer OPN levels are known to increase (as a result of multiple aberrant signaling pathways). We propose that following signaling via OPN, activated phospho-Akt phosphorylates Merlin. Phosphorylated Merlin is targeted for proteasomal degradation. Thus, with the advancement of breast cancer, the increase in OPN decreases stability of Merlin, resulting in an overall decreased pool of Merlin in the cells. This disrupts the normal physiological balance between Merlin and OPN. This vicious cycle promotes malignant progression of breast cancer. Our overall objectives are (i) to elucidate the significance of Merlin in breast cancer and, (ii) to understand the mechanism of reciprocal regulation of Merlin and OPN in breast cancer. Towards this, we have proposed the following Specific Aims. Specific Aim 1: Test the hypothesis that by modulating Merlin levels we can regulate the malignant behavior of breast cancer cells. Specific Aim 2: Understand the mechanism of reciprocal regulation of Merlin and OPN in breast cancer. Specific Aim 3: Determine the correlation between expression of OPN and Merlin in patient-derived breast cancer specimens. Expected outcome & Impact: The proposed studies will lead to a better understanding of the role of Merlin in breast cancer progression & will reveal a yin-and-yang relationship between the OPN and Merlin. The ability to potentially use Akt/PI-3-kinase and proteasome inhibitors to stabilize Merlin protein is a treatment modality that can be explored in patients to reinstate the growth-inhibitory activity of Merlin. PUBLIC HEALTH RELEVANCE: The proposed studies will lead to a better understanding of the role of the tumor suppressor, Merlin, in breast cancer progression. Our research will reveal a yin-and-yang relationship between the oncoprotein, OPN and the tumor suppressor, Merlin. Our studies will lay the foundation for considering the use of Akt/PI-3-kinase and proteasome inhibitors to stabilize Merlin protein as treatment options for breast cancers that have lost the expression of Merlin concomitant with a gain in OPN expression.

描述（由申请人提供）：肿瘤细胞表达的癌蛋白骨桥蛋白（OPN）会增强其恶性特性，特别是通过影响其生长、侵袭和转移的能力。我们的研究表明，OPN 可能通过靶向乳腺癌细胞中的降解来下调肿瘤抑制蛋白 Merlin 的蛋白水平。 Merlin 是一种肿瘤抑制基因，已在神经系统的各种肿瘤类型中得到充分表征。在神经系统肿瘤中，Merlin 介导接触抑制、侵袭、细胞生长并阻碍增殖。最近的证据还表明，在翻译后修饰（包括 Akt 介导的磷酸化和泛素化）后，Merlin 蛋白在上述肿瘤类型中迅速降解。 Merlin 正在接受乳腺癌方面的研究。有趣的是，我们还发现Merlin对OPN有负向调节作用。基于这些发现，我们假设 Merlin 和 OPN 相互调节。两种蛋白质水平之间的平衡对于维持非恶性细胞行为至关重要。 Merlin 会控制未转化细胞中的 OPN 水平。已知在乳腺癌发病过程中，OPN 水平会增加（由于多种异常信号传导途径）。我们建议，在通过 OPN 发出信号后，激活的磷酸-Akt 会使 Merlin 磷酸化。磷酸化 Merlin 是蛋白酶体降解的目标。因此，随着乳腺癌的进展，OPN的增加降低了Merlin的稳定性，导致细胞中Merlin池的整体减少。这破坏了 Merlin 和 OPN 之间的正常生理平衡。这种恶性循环促进了乳腺癌的恶性进展。我们的总体目标是 (i) 阐明 Merlin 在乳腺癌中的重要性，以及 (ii) 了解 Merlin 和 OPN 在乳腺癌中相互调节的机制。为此，我们提出了以下具体目标。 具体目标 1：检验以下假设：通过调节 Merlin 水平，我们可以调节乳腺癌细胞的恶性行为。 具体目标2：了解Merlin和OPN在乳腺癌中相互调节的机制。 具体目标 3：确定患者来源的乳腺癌样本中 OPN 和 Merlin 表达之间的相关性。 预期结果和影响：拟议的研究将有助于更好地了解 Merlin 在乳腺癌进展中的作用，并将揭示 OPN 和 Merlin 之间的阴阳关系。使用 Akt/PI-3 激酶和蛋白酶体抑制剂来稳定 Merlin 蛋白的能力是一种可以在患者中探索的治疗方式，以恢复 Merlin 的生长抑制活性。 公共健康相关性：拟议的研究将有助于更好地了解肿瘤抑制因子 Merlin 在乳腺癌进展中的作用。我们的研究将揭示癌蛋白 OPN 和肿瘤抑制因子 Merlin 之间的阴阳关系。我们的研究将为考虑使用 Akt/PI-3 激酶和蛋白酶体抑制剂来稳定 Merlin 蛋白作为治疗方案奠定基础，用于治疗 Merlin 表达缺失同时 OPN 表达增加的乳腺癌。