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ERα-浸润性癌以及高级别导管原位癌（DCIS）中高表达，因此可能在乳腺癌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?- 乳腺癌细胞的生长和转移，并抑制 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 的不同作用是两种不同途径的结果：在 ER?- 中，它可能通过与晚期糖基化终末产物 (RAGE) 受体结合并反式激活 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。 ERα-的侵袭性特征（尤其是三阴性乳腺癌）以及ERα+乳腺癌的耐药性的产生显着导致患者死亡；因此，了解 S100A7 如何调节 ER?- 和 ER?+ 乳腺癌的差异效应至关重要。为此，我们将利用转基因和敲除小鼠模型系统，采用创新的多学科方法来分析S100A7的作用和分子机制。在目标1中，我们将进一步分析不同级别和亚型的乳腺癌组织微阵列中S100A7的表达，特别是三阴性乳腺癌。在目标 2 中，我们将进一步表征 S100A7 在体内小鼠模型中调节 ER?+ 和 ER?- 细胞生长和转移中的作用。在目标 3 中，我们将在转基因和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 介导的增强 ERα- 细胞生长和转移并抑制 ERα+ 细胞增殖和迁移的分子机制。从这些研究中获得的见解可能有助于开发针对高侵袭性 ER?- 和耐药 ER?+ 乳腺癌的新颖和创新疗法。

项目成果

Conditioning solid tumor microenvironment through inflammatory chemokines and S100 family proteins.

通过炎症趋化因子和 S100 家族蛋白调节实体瘤微环境。

• DOI: 10.1016/j.canlet.2015.05.002
• 发表时间: 2015-08-28
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: M. Nasser;Mohamad Elbaz;D. Ahirwar;R. Ganju
• 通讯作者: R. Ganju

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

大麻素作为癌症治疗剂：现状和未来影响。

• 发表时间: 2014-08-15
• 作者: Chakravarti, Bandana;Ravi, Janani;Ganju, Ramesh K
• 通讯作者: Ganju, Ramesh K

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

FAAH 抑制通过下调 EGF/EGFR 通路增强 anandamide 介导的非小细胞肺癌抗肿瘤作用。

• 发表时间: 2014-05-15
• 作者: Ravi, Janani;Sneh, Amita;Shilo, Konstantin;Nasser, Mohd W;Ganju, Ramesh K
• 通讯作者: Ganju, Ramesh K

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

脂肪酸结合蛋白5通过增强表皮生长因子受体稳定性来促进三阴性乳腺癌细胞的转移潜力。

• 发表时间: 2015-03-20
• 作者: Powell, Catherine A;Nasser, Mohd W;Zhao, Helong;Wochna, Jacob C;Zhang, Xiaoli;Shapiro, Charles;Shilo, Konstantin;Ganju, Ramesh K
• 通讯作者: Ganju, Ramesh K

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

大麻素受体 2 激动剂通过下调 EGFR 通路抑制巨噬细胞诱导的非小细胞肺癌 EMT。

• 发表时间: 2016
• 影响因子: 4.6
• 作者: Ravi, Janani;Elbaz, Mohamad;Wani, Nissar A;Nasser, Mohd W;Ganju, Ramesh K
• 通讯作者: Ganju, Ramesh K