Regulation of Snail in breast cancer progression and metastasis

Snail在乳腺癌进展和转移中的调节作用

• 批准号: 9259915
• 负责人: Binhua P Zhou
• 金额: $ 27.74万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259915
• 关键词: Address; Affect; BRCA1 gene; Binding Proteins; Brain; Breast; Breast Cancer Cell; CCL2 gene; Caenorhabditis elegans; Cancer cell line; Cells; Cellular Stress; Characteristics; Chromatin; Clinical; Complex; Data; Development; Disease; Distant Metastasis; Down-Regulation; E-Cadherin; Endoplasmic Reticulum; Environment; Enzymes; Epithelial; Exhibits; Fostering; Gene Silencing; Glycogen Synthase Kinase 3; Goals; Growth Factor; Homeostasis; Human; IL8 gene; Immune; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-6; Intervention; Intestines; Intrinsic factor; KDM1A gene; Knowledge; Leukocytes; Location; Lung; Lymphocyte; Malignant Neoplasms; Mammary Neoplasms; Mediating; Medical Oncologist; Mesenchymal; Molecular; Mus; Mutation; Neoplasm Metastasis; Outcome; Pathologist; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Proteins; Public Health; Reagent; Recording of previous events; Recruitment Activity; Recurrence; Regulation; Repression; Research; Role; Sampling; Signal Pathway; Signal Transduction; Site; Snails; Stromal Neoplasm; Talents; Testing; Therapeutic Intervention; Tissues; Up-Regulation; cancer stem cell; cancer subtypes; cancer therapy; cell injury; chemokine; chromatin modification; cytokine; endoplasmic reticulum stress; experimental study; gene repression; genome wide association study; in vivo; inhibitor/antagonist; innovation; insight; macrophage; malignant breast neoplasm; multidisciplinary; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; paracrine; prevent; programs; promoter; protein expression; public health relevance; response; snail protein; success; targeted treatment; trait; tumor; tumor microenvironment; tumor progression; ubiquitin isopeptidase; ubiquitin-protein ligase; wound; young woman

DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) exhibits an aggressive clinical history, with development of recurrence, distant metastasis, shorter survival, and usually occurs in young women. BLBC intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and cancer stem cell (CSC)-like features, suggesting that activation of EMT program generates high-grade invasive cells with CSC-like traits in BLBC. Our long-term goal is to discover the intrinsic factors within tumor cells and the extrinsic signals from tumor microenvironments that regulate EMT, and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last several years, we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT; our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However, how the extrinsic tumor milieu of BLBC is initiated and built up, despite its paramount importance, remains unaddressed. Recently, we found that expression of the X-box binding protein (XBP1) was significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2, a major chemokine for tumor associated macrophages (TAMs) and lymphocytes. XBP1 is a key molecule in the most conserved "unfolded-protein response" (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in "unresolved ER stress", which signals endogenous cellular injury, triggering leukocyte infiltration, and a significant boost of inflammatory responses in target tissues. We hypothesize that the loss of XBP1 by Snail-mediated repression ignites an "inside out" signal for recruiting TAMs and lymphocytes, which establish an inflammatory/wound stroma to further boost EMT and cultivate CSC-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis using a newly developed specific Snail inhibitor. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms responsible for Snail-mediated XBP1 repression in BLBC; (2) to delineate why loss of XBP1 enhances inflammation in BLBC; and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant, because it will not only open a new paradigm that significantly affects our views on the co- evolvement of tumor cells and their microenvironments in breast cancer progression and metastasis but will also lay groundwork for developing new therapeutic strategies against this disease.

描述（由申请人提供）：基底样乳腺癌（BLBC）表现出侵袭性临床病史，伴有复发、远处转移、生存期缩短，通常发生于年轻女性。BLBC本身具有许多上皮-间质转化（EMT）特征和癌干细胞（CSC）样特征，表明EMT程序的激活在BLBC中产生具有CSC样特征的高级别侵袭性细胞。我们的长期目标是发现肿瘤细胞内的内在因素和调节EMT的肿瘤微环境的外在信号，并确定可能作为治疗这种致命疾病的药物靶点的分子。在过去的几年中，我们系统地研究了Snail的作用和Snail抑制BLBC中E-cadherin表达的分子机制。我们的研究清楚地表明，Snail是肿瘤细胞内负责EMT的关键内在因子之一;我们的研究还表明，炎症肿瘤微环境为EMT提供了外在信号。然而，BLBC的外源性肿瘤环境是如何启动和建立的，尽管其至关重要，仍然没有得到解决。最近，我们发现X盒结合蛋白（XBP 1）的表达显着减少BLBC从人类乳腺肿瘤样品和小鼠乳腺癌组织。Snail抑制了XBP 1的表达，并导致CCL 2的显著上调，CCL 2是肿瘤相关巨噬细胞（TAM）和淋巴细胞的主要趋化因子。XBP 1是最保守的“未折叠蛋白反应”（UPR）信号通路中的关键分子，细胞利用该通路来科普内质网（ER）中的环境和细胞应激。XBP 1的缺失导致“未解决的ER应激”，其发出内源性细胞损伤的信号，触发白细胞浸润，并显著增强靶组织中的炎症反应。我们假设，通过Snail介导的抑制作用导致的XBP 1的丢失引发了招募TAM和淋巴细胞的“由内而外”信号，TAM和淋巴细胞建立了炎症/伤口基质，以通过提供额外的细胞因子和生长因子进一步促进EMT并在BLBC中培养CSC样性状。该提案的目的是表征蜗牛对XBP 1的抑制，并探索将破坏这种恶性循环的治疗干预，从而使用新开发的特异性蜗牛抑制剂恢复ER稳态。在强有力的初步数据的指导下，我们将通过追求三个具体目标来验证这一假设：（1）确定负责Snail介导的BLBC中XBP 1抑制的分子机制;（2）描述为什么XBP 1的缺失会增强BLBC中的炎症;（3）阐明XBP 1在体内的功能作用。我们的建议是创新和重要的，因为它不仅将打开一个新的范式，显着影响我们对乳腺癌进展和转移中肿瘤细胞及其微环境的共同演变的看法，而且还将为开发针对这种疾病的新治疗策略奠定基础。

项目成果

TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion.

• DOI: 10.1038/sj.bjc.6605530
• 发表时间: 2010-02-16
• 期刊: British journal of cancer
• 影响因子: 8.8

Activation of β-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters.

• DOI: 10.1186/1471-2407-11-49
• 发表时间: 2011-02-01
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Li J;Zhou BP
• 通讯作者: Zhou BP

The Role of Snail in EMT and Tumorigenesis.

• DOI: 10.2174/15680096113136660102
• 发表时间: 2013-11
• 期刊: Current cancer drug targets
• 影响因子: 3
• 作者: Wang Y;Shi J;Chai K;Ying X;Zhou BP
• 通讯作者: Zhou BP

The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells.

• DOI: 10.1016/j.celrep.2013.08.030
• 发表时间: 2013-10-17
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Wu Y;Wang Y;Yang XH;Kang T;Zhao Y;Wang C;Evers BM;Zhou BP
• 通讯作者: Zhou BP

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.

EGFR 磷酸化并抑制肺癌中的肺肿瘤抑制因子 GPRC5A

• DOI: 10.1186/1476-4598-13-233
• 发表时间: 2014-10-14
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Lin X;Zhong S;Ye X;Liao Y;Yao F;Yang X;Sun B;Zhang J;Li Q;Gao Y;Wang Y;Liu J;Han B;Chin YE;Zhou BP;Deng J
• 通讯作者: Deng J