The role of the mucin Muc4 signaling in breast cancer formation and progression

粘蛋白 Muc4 信号在乳腺癌形成和进展中的作用

• 批准号: 8534935
• 负责人: Jason Hatakeyama
• 金额: $ 3.5万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534935
• 关键词: Animals; Anoikis; Automobile Driving; Behavior; Biochemical; Biological Assay; Biology; Breast; Breast Melanoma; Cancer Biology; Cancer Patient; Carcinoma; Cell Culture Techniques; Cell Line; Cells; Chemicals; Chemosensitization; Collaborations; Collection; Coupled; Critical Pathways; Cultured Cells; Diagnostic Neoplasm Staging; Dissection; Doxycycline; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Fatty acid glycerol esters; Fibroblasts; Future; Growth; Histologic; Hyperplasia; In Vitro; Integral Membrane Protein; Lesion; Light; Lung; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Measures; Melanoma Cell; Membrane; Mesenchymal; Methods; Modeling; Molecular; Mucins; Mus; Neoplasm Metastasis; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Outcome; Pathologist; Pathology; Patients; Phenotype; Play; Premalignant; Primary Neoplasm; Process; Property; Proteins; Relative (related person); Reporting; Role; Sampling; Series; Signal Pathway; Signal Transduction; Staging; Structure; Tetracycline Control; Tetracyclines; Therapeutic; Therapeutic Intervention; Tissue Sample; Tissues; Training; Transplantation; Tumor-Associated Process; Work; cancer cell; cell growth; cell motility; cell type; combat; drinking water; in vivo; lymph nodes; malignant breast neoplasm; malignant state; matrigel; meetings; metaplastic cell transformation; migration; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; prognostic; research study; symposium; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The membrane mucin Muc4 is overexpressed in a variety of carcinomas. Some evidence has accumulated suggesting that Muc4 may have roles in both the initial transformation of healthy epithelia to early hyperplastic phenotypes and in latr transitions to highly invasive and metastatic states. For example, it has been reported that Muc4 is overexpressed and mislocalized in 20% of local breast tumors compared to patient-matched normal tissue samples. Coupled with observations that Muc4 expression is sufficient to transform mouse fibroblasts, these observations raise the possibility that Muc4 plays an active role in initiating events in breast cancer. It has also been reported that Muc4 protein is highly upregulated in the majority of breast cancer lymph node metastases compared to patient-matched primary tumors, pointing to a role in later events related to progression to metastasis. The studies outlined here seek to rigorously assess the roles of Muc4 in breast cancer onset and progression using the MCF10A progression series, an isogenic series of cell lines modeling normal, hyperplastic, and malignant breast tissue. The hypothesis driving the proposed studies is that Muc4 overexpression engages specific signaling pathways to promote cellular transitions to progressively more malignant states. The study will be broken down into two specific aims. Specific Aim 1 will characterize the impact of Muc4 overexpression on the in vitro growth properties of the MCF10A progression series cell lines. In these experiments, the MCF10A progression series cells will be stably transduced with tetracycline-inducible Muc4, and the impact of Muc4 on cellular transformation, proliferation, motility, and invasiveness will be measured, along with Muc4-dependent potentiation of growth and survival signaling pathways. These studies will also examine the impact of Muc4 overexpression on the growth of cells in three dimensional cell cultures using the Matrigel matrix. Specific Aim 2 will determine whether Muc4 overexpression induces transitions from less malignant to more malignant states in the normal mammary environment in vivo. The cell lines created in Aim 1 will be orthotopically introduced into nude mouse mammary fat pads, and tumor latency, size, and rate of metastasis will be measured without and with Muc4 induction. Histological analysis of collected tissues will be employed to assess Muc4-induced transitions in cancer stage. The successful completion of the proposed studies could implicate Muc4 as a novel target for future therapeutic intervention in breast cancer. Training opportunities for the PI include classes in mouse biology, pathology and surgery, weekly meetings with the UCD mammary gland biology and pathology group, an extensive series of seminars, tumor boards and symposia in cancer biology and therapeutics, and close collaboration with pathologists and statisticians. Results emerging from the study will be presented at a national conference in cancer biology in Year 3.

描述（由申请人提供）：膜粘蛋白Muc4在多种癌症中过度表达。一些证据表明，Muc4 可能在健康上皮细胞向早期增生表型的最初转变以及后来向高度侵袭性和转移状态的转变中发挥作用。例如，据报道，与患者匹配的正常组织样本相比，Muc4 在 20% 的局部乳腺肿瘤中过度表达和错误定位。结合 Muc4 表达足以转化小鼠成纤维细胞的观察结果，这些观察结果提出了 Muc4 在乳腺癌起始事件中发挥积极作用的可能性。据报道，与患者匹配的原发肿瘤相比，Muc4 蛋白在大多数乳腺癌淋巴结转移中高度上调，表明在与进展至转移相关的后续事件中发挥作用。本文概述的研究旨在使用 MCF10A 进展系列（模拟正常、增生和恶性乳腺组织的同基因细胞系系列）严格评估 Muc4 在乳腺癌发病和进展中的作用。推动这项研究的假设是，Muc4 过度表达会参与特定的信号通路，促进细胞逐渐向更恶性的状态转变。该研究将分为两个具体目标。具体目标 1 将描述 Muc4 过表达对 MCF10A 进展系列细胞系体外生长特性的影响。在这些实验中，MCF10A进展系列细胞将用四环素诱导的Muc4稳定转导，并且将测量Muc4对细胞转化、增殖、运动和侵袭性的影响，以及生长和存活信号通路的Muc4依赖性增强。这些研究还将使用 Matrigel 基质检验 Muc4 过度表达对三维细胞培养物中细胞生长的影响。具体目标 2 将确定 Muc4 过度表达是否会在体内正常乳腺环境中诱导从恶性程度较低的状态转变为恶性程度较高的状态。将目标 1 中创建的细胞系原位引入裸鼠乳腺脂肪垫中，并在没有或有 Muc4 诱导的情况下测量肿瘤潜伏期、大小和转移率。对收集的组织进行组织学分析将用于评估 Muc4 诱导的癌症阶段转变。拟议研究的成功完成可能意味着 Muc4 作为未来乳腺癌治疗干预的新靶点。 PI 的培训机会包括小鼠生物学、病理学和外科课程、与 UCD 乳腺生物学和病理学小组的每周会议、一系列广泛的研讨会、肿瘤委员会和癌症生物学和治疗学专题讨论会，以及与病理学家和统计学家的密切合作。该研究的结果将在第三年的全国癌症生物学会议上公布。