Role of S100A7 in breast cancer progression and metastasis

S100A7 在乳腺癌进展和转移中的作用

• 批准号: 8699159
• 负责人: Ramesh K. Ganju
• 金额: $ 29.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699159
• 关键词: Advanced Glycosylation End Products; B-Lymphocytes; Binding; Biological Models; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Carcinoma; Cell Proliferation; Cells; Characteristics; Development; Drug resistance; Epidermal Growth Factor Receptor; Growth; Hyperplasia; Innovative Therapy; Knockout Mice; Lead; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Metastatic Neoplasm to the Bone; Molecular; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Osteoclasts; Outcome; Pathway interactions; Patients; Phenotype; Play; Prevention; Role; S100A7; Series; Signal Transduction; TCF7L2 gene; Tissue Microarray; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Tissue; Work; cell motility; extracellular; human ESR1 protein; in vivo; innovation; insight; malignant breast neoplasm; migration; mortality; mouse model; new therapeutic target; novel; osteoclastogenesis; overexpression; psoriasin; receptor; triple-negative invasive breast carcinoma; tumor growth; tumor microenvironment; tumor progression; Advanced Glycosylation End Products; B-Lymphocytes; Binding; Biological Models; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Carcinoma; Cell Proliferation; Cells; Characteristics; Development; Drug resistance; Epidermal Growth Factor Receptor; Growth; Hyperplasia; Innovative Therapy; Knockout Mice; Lead; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Metastatic Neoplasm to the Bone; Molecular; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Osteoclasts; Outcome; Pathway interactions; Patients; Phenotype; Play; Prevention; Role; S100A7; Series; Signal Transduction; TCF7L2 gene; Tissue Microarray; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Tissue; Work; cell motility; extracellular; human ESR1 protein; in vivo; innovation; insight; malignant breast neoplasm; migration; mortality; mouse model; new therapeutic target; novel; osteoclastogenesis; overexpression; psoriasin; receptor; triple-negative invasive breast carcinoma; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): S100A7 is highly expressed in ER?- invasive carcinoma, as well as in high grade ductal carcinomas in situ (DCIS), and therefore may play an important role in breast cancer progression and metastasis. Our preliminary studies indicate that S100A7 has differential effects on ER?+ and ER?- cells; it enhances growth and metastasis in ER?- and inhibits growth in ER?+ breast cancer cells. However, it remains to be determined if and how S100A7 modulates differential effects in ER?+ and ER?- breast cancer subtypes. Our central hypothesis is that the differential effects of S100A7 are a result of two different pathways: in ER?-, it may modulate the tumor microenvironment by binding to receptor for advance glycation end products (RAGE) and transactivating EGFR; in ER?+ cells, it may regulate the 2-catenin pathway. The mortality of patients is significantly caused by the invasive characteristics of ER?-, especially in triple-negative breast cancers, and the development of drug resistance in ER?+ breast cancers; as a result, understanding how S100A7 may modulate differential effects in ER?- and ER?+ breast cancers is of fundamental importance. To this end, we will use an innovative, multi-disciplinary approach to analyze the role and molecular mechanisms of S100A7, taking advantage of transgenic and knockout mouse model systems. In Aim 1, we will further analyze S100A7 expression in breast cancer tissue microarrays in different grades and subtypes, especially triple-negative breast cancers. In Aim 2, we will further characterize the role of S100A7 in modulating the growth and metastasis of ER?+ and ER?- cells in in vivo mouse models. In Aim 3, we will analyze the role of S100A7 in breast cancer progression and metastasis in transgenic and knockout mouse model systems. Finally, in Aim 4, we will delineate the S100A7-mediated molecular mechanisms that enhance growth and metastasis of ER?- cells and inhibit cell proliferation and migration of ER?+ cells. Insight gained from these studies may help in developing novel and innovative therapies for highly invasive ER?- and drug resistant ER?+ breast cancers.

描述（由申请人提供）：S100A7在ER？ - 浸润性癌以及高级导管癌（DCIS）中高度表达，因此在乳腺癌进展和转移中可能起重要作用。我们的初步研究表明，S100A7对ER？+和ER？ - 细胞具有不同的影响。它增强了ER的生长和转移？ - 并抑制ER？+乳腺癌细胞的生长。但是，尚待确定S100A7是否以及如何调节ER？+和ER？ - 乳腺癌亚型的差异作用。我们的中心假设是，S100A7的差异效应是两种不同途径的结果：在ER？ - 它可以通过与受体结合来调节肿瘤微环境，以进行预先的糖化终端产物（RAGE）和反式激活EGFR；在ER？+细胞中，它可能调节2-catenin途径。患者的死亡率显着由ER的侵入性特征引起，尤其是在三阴性乳腺癌中，以及ER？+乳腺癌中耐药性的发展；结果，了解S100A7如何调节ER中的差异效应？ - ER？+乳腺癌至关重要。为此，我们将使用一种创新的多学科方法来利用转基因和基因敲除小鼠模型系统来分析S100A7的作用和分子机制。在AIM 1中，我们将进一步分析不同等级和亚型的乳腺癌组织微阵列中的S100A7表达，尤其是三阴性乳腺癌。在AIM 2中，我们将进一步表征S100A7在调节体内小鼠模型中ER？+和ER ？-细胞的生长和转移中的作用。在AIM 3中，我们将分析S100A7在转基因和基因敲除小鼠模型系统中的作用。最后，在AIM 4中，我们将描述S100A7介导的分子机制，从而增强ER？ - 细胞的生长和转移，并抑制ER？+细胞的细胞增殖和迁移。从这些研究中获得的洞察力可能有助于开发高度侵入性ER的新颖和创新疗法以及耐药性ER？+乳腺癌。