Characterization of WWOX, the Cancer Gene Spanning FRA16D

跨越 FRA16D 的癌症基因 WWOX 的表征

• 批准号: 8265684
• 负责人: C. Marcelo Aldaz
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265684
• 关键词: Ablation; Affect; Binding; Bone Development; Bone Diseases; Bone Marrow; Breast; Breast Cancer Cell; Cancer Patient; Cell Adhesion; Cell surface; Cells; Complex; Development; Disease; Employee Strikes; Engineering; Epithelial; Event; Gene Targeting; Genes; Growth; Growth and Development function; Homeostasis; Injection of therapeutic agent; Integrins; Lesion; Lytic Metastatic Lesion; Mammary Tumorigenesis; Mammary gland; Matrix Metalloproteinases; Metastatic Neoplasm to the Bone; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Nuclear Translocation; Oncogene Proteins; Oncogenes; Osteoblasts; Osteogenesis; Osteolysis; Osteolytic; Pain; Pathological fracture; Pathway interactions; Patients; Phenotype; Play; Prevention; Proliferating; Property; Proteins; Quality of life; Research; Role; Signal Transduction; Site; Skeleton; Staging; Stromal Cells; Testing; Therapeutic; Therapeutic Intervention; Transactivation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vascular Endothelial Growth Factors; base; bone; functional restoration; in vivo; insight; malignant breast neoplasm; mutant; novel; osteoblast differentiation; osteogenic; osteopontin; overexpression; parathyroid hormone-related protein; protein expression; public health relevance; restoration; spinal cord compression; transcription factor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The development of bone metastases is one of the most debilitating complications of advanced breast cancer. Patients suffer from severe pain, spontaneous fractures and possible spinal cord compression caused by development of osteolytic lesions. We don't understand how breast cancer cells develop the ability to metastasize and proliferate in bone. As a consequence, therapeutic options at this advanced stage of breast cancer are extremely limited. Breast cancer bone metastatic cells undergo striking changes, expressing genes involved in bone development such as OPN, MMPs, VEGF, all known markers of tumor growth, invasion and metastasis. Importantly, these genes are controlled by the master regulator of bone formation RUNX2, and RUNX2 becomes overexpressed in breast cancer metastatic cells. We identified that the WWOX tumor suppressor protein physically interacts with and represses RUNX2 transcriptional activity. We hypothesize that loss of WWOX expression (a common event in breast cancer) is key for the progression of breast cancer cells towards development of a bone metastatic phenotype. Our current research suggests that loss of WWOX in breast cancer cells leads to unrestrained RUNX2 activity, Osteopontin overexpression and these maybe key determinants for metastasis development. We expect aborting development of bone metastases by restoring function of the WWOX-RUNX2 axis. We have also created a conditional Wwox KO mouse that will allow in vivo study of effects in mammary gland growth, tumor development and metastasis. Therefore we will pursue the following Specific Aims: Aim 1: We will A. determine whether WWOX depletion alters the phenotype of normal mammary epithelial and non-metastatic breast cancer cells and B. determine the effects of restoring WWOX expression in metastatic breast cancer cells. Aim 2: A. To determine whether WWOX restoration suppresses spontaneous bone metastasis and osteolytic bone disease in breast cancer metastatic cells. B. To determine if WWOX depletion induces a metastatic and osteolytic phenotype in non-metastatic breast cancer cells. C. To determine whether WWOX influences the ability of breast cancer cells to crosstalk with the bone microenvironment by affecting osteogenic differentiation. Aim 3: To determine whether the integrity of the WWOX-RUNX2 physical interaction is relevant for impeding bone metastases and associated osteolytic disease. Aim 4: To determine whether targeted Wwox ablation in the mammary gland leads to enhanced mammary tumorigenesis and increases metastasis. The proposed studies will provide novel information on the mechanistic basis of bone metastasis development and identify potential novel targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: We do not understand how breast cancer cells develop the ability to metastasize and proliferate in bone; therapeutic options at this advanced stage of breast cancer are extremely limited. We hypothesized that loss of expression of the tumor suppressor WWOX in breast cancer cells leads to unrestrained activity of the RUNX2 transcription factor and that this maybe a key determinant of metastasis development. The proposed studies will test this hypothesis, provide novel information on the mechanistic basis of bone metastasis development and identify potential novel targets for therapeutic intervention.

描述（由申请人提供）：骨转移的发展是晚期乳腺癌最令人衰弱的并发症之一。 患者患有严重的疼痛，自发性骨折以及造骨病变引起的可能的脊髓压缩。 我们不了解乳腺癌细胞如何发展骨骼转移和增殖的能力。 因此，在乳腺癌晚期阶段的治疗选择极为有限。 乳腺癌骨转移细胞发生惊人的变化，表达涉及骨骼发育的基因，例如OPN，MMP，VEGF，所有已知的肿瘤生长，侵袭和转移标记。 重要的是，这些基因由骨形成runx2的主要调节因子控制，Runx2在乳腺癌转移细胞中过表达。 我们确定WWOX肿瘤抑制蛋白与RUNX2转录活性有物理相互作用并抑制。 我们假设WWOX表达的丧失（乳腺癌中的常见事件）是乳腺癌细胞向发展骨转移表型发展的关键。 我们目前的研究表明，乳腺癌细胞中WWOX的丧失会导致runx2活性，骨桥蛋白过表达以及这些转移发展的关键决定因素。 我们预计通过恢复WWOX-RUNX2轴的功能来流产骨转移。 我们还创建了有条件的WWOX KO小鼠，该小鼠将允许体内研究乳腺生长，肿瘤发育和转移的影响。 因此，我们将追求以下特定目的：目标1：我们将A.确定WWOX耗竭是否改变了正常乳腺上皮和非转移性乳腺癌细胞的表型，并确定B。确定恢复转移性乳腺癌细胞中WWOX表达的影响。 目标2：A。确定WWOX恢复是否抑制乳腺癌转移性细胞中自发性骨转移和骨骨病。 B.确定WWOX耗竭是否诱导非转移性乳腺癌细胞中的转移性和溶性表型。 C.确定WWOX是否通过影响成骨分化而与骨微环境串扰的乳腺癌细胞能力。 目的3：确定WWOX-RUNX2物理相互作用的完整性是否与阻碍骨转移和相关骨气疾病有关。 目的4：确定在乳腺中靶向的WWOX消融是否导致乳腺肿瘤发生增强并增加转移。 拟议的研究将提供有关骨转移发育机械基础的新信息，并确定潜在的治疗干预靶标。 公共卫生相关性：我们不了解乳腺癌细胞如何发展骨骼转移和增殖的能力。在这个高级乳腺癌阶段的治疗选择极为有限。 我们假设乳腺癌细胞中肿瘤抑制剂WWOX表达的丧失导致Runx2转录因子的活性不受约束，并且这可能是转移发展的关键决定因素。 拟议的研究将检验这一假设，提供有关骨转移发展的机械基础的新信息，并确定潜在的治疗干预措施。