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: 8841515
• 负责人: Ramesh K. Ganju
• 金额: $ 0.91万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841515
• 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

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(申请人提供)：S100A7在ER？浸润性癌和高级别导管原位癌中高表达，因此可能在乳腺癌的进展和转移中发挥重要作用。我们的初步研究表明，S100A7对ER？+和ER？-细胞有不同的作用；它促进ER？-细胞的生长和转移，抑制ER？+乳腺癌细胞的生长。然而，S100A7是否以及如何调节ER？+和ER？-乳腺癌亚型的差异效应仍有待确定。我们的中心假设是，S100A7的不同作用是两条不同途径的结果：在ER？-中，它可能通过与高级糖基化终产物受体(RAGE)结合并反式激活EGFR来调节肿瘤微环境；在ER？+细胞中，它可能调节2-连环蛋白途径。ER？-的侵袭特性，特别是在三阴性乳腺癌中的侵袭特性以及ER？+乳腺癌耐药的形成是导致患者死亡的重要原因，因此，了解S100A7如何调节ER？-和ER？+乳腺癌的差异效应具有重要意义。为此，我们将使用一种创新的、多学科的方法来分析S100A7的作用和分子机制，利用转基因和基因敲除小鼠模型系统。在目标1中，我们将进一步分析S100A7在不同级别和亚型的乳腺癌组织芯片中的表达，特别是三阴性乳腺癌。在目标2中，我们将进一步研究S100A7在体内小鼠模型中对ER？+和ER？-细胞生长和转移的调控作用。在目标3中，我们将在转基因和基因敲除小鼠模型系统中分析S100A7在乳腺癌进展和转移中的作用。最后，在目标4中，我们将描述S100A7介导的促进ER？-细胞的生长和转移以及抑制ER？+细胞的增殖和迁移的分子机制。从这些研究中获得的洞察力可能有助于开发治疗高侵袭性ER？和耐药ER？+乳腺癌的新的和创新的疗法。

项目成果

FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway.

• DOI: 10.18632/oncotarget.1723
• 发表时间: 2014-05-15
• 期刊: Oncotarget
• 作者: Ravi J;Sneh A;Shilo K;Nasser MW;Ganju RK
• 通讯作者: Ganju RK

Fatty acid binding protein 5 promotes metastatic potential of triple negative breast cancer cells through enhancing epidermal growth factor receptor stability.

• DOI: 10.18632/oncotarget.3442
• 发表时间: 2015-03-20
• 期刊: Oncotarget
• 作者: Powell CA;Nasser MW;Zhao H;Wochna JC;Zhang X;Shapiro C;Shilo K;Ganju RK
• 通讯作者: Ganju RK

Cannabinoids as therapeutic agents in cancer: current status and future implications.

• DOI: 10.18632/oncotarget.2233
• 发表时间: 2014-08-15
• 期刊: Oncotarget
• 作者: Chakravarti B;Ravi J;Ganju RK
• 通讯作者: Ganju RK

Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.

• DOI: 10.1002/mc.22451
• 发表时间: 2016-12
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: Ravi J;Elbaz M;Wani NA;Nasser MW;Ganju RK
• 通讯作者: Ganju RK