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Deciphering COX-2/SEMA7A dependent mechanisms of breast tumor progression.

破译乳腺肿瘤进展的 COX-2/SEMA7A 依赖性机制。

基本信息

批准号：
10171400
负责人：
Traci Lyons
金额：
$ 35.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-19 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171400
关键词：
3-Dimensional Adherence Adult Affect Back Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Prevention Cancer cell line Cell Line Cell Proliferation Cessation of life Childbirth Clinical Trials Collagen Color Colorado Data Data Set Development Diagnosis Down-Regulation Endothelial Cells Enzymes Extracellular Matrix Feedback Gene Expression Profiling Genes Growth Human Immunity Implant Inflammatory Isogenic transplantation Lactation Lead Lung Lymphangiogenesis Lymphatic Endothelium Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Mediator of activation protein Messenger RNA Metastatic Neoplasm to the Lung Modeling Mus Neoplasm Metastasis Nulliparity Outcome PTGS2 gene Pathway interactions Patients Physiological Processes Postpartum Period Proteins Publishing Recurrence Research Role Sampling Semaphorins Signal Transduction Signaling Molecule Testing The Cancer Genome Atlas Tissues Toxic effect Tumor Cell Invasion Universities Up-Regulation Vascular remodeling Woman Xenograft procedure aged breast cancer diagnosis breast cancer progression breast tumorigenesis cancer cell cancer invasiveness clinically relevant cohort cyclooxygenase 2 density extracellular improved outcome knock-down lymph nodes lymphatic vessel mRNA Expression malignant breast neoplasm migration monolayer mouse model neoplastic cell neurodevelopment neuron development new therapeutic target novel overexpression patient derived xenograft model postpartum breast cancer pregnant protein expression receptor small hairpin RNA therapeutic target transcriptome tumor tumor growth tumor microenvironment tumor progression wound healing young woman

项目摘要

Background: Postpartum breast cancers, defined as breast cancers diagnosed within 5-10 years of last childbirth, are more than twice as likely to become metastatic and result in death. This devastating diagnosis affects thousands of young women annually. Our previous research revealed that non-invasive breast tumor cells become invasive and metastatic in postpartum mice compared to controls in nulliparous mice. We also revealed a novel feedback loop involving collagen mediated upregulation of COX-2, which mediates invasion and metastasis in postpartum mice. Subsequent gene expression analysis revealed a significant and specific upregulation of SEMA7A mRNA in postpartum breast tumor cells. The SEMA7A gene encodes for semaphorin 7a (Sema7a), a signaling molecule that drives neural development, immunity, and tissue remodeling in the lung. Our preliminary data demonstrate that silencing of SEMA7A cell line derived postpartum breast cancer xenografts delays growth, progression to invasive cancer, and reduces lymphangiogenesis in the tumor microenvironment. In addition, we have analyzed our young women’s breast cancer cohort to reveal that SEMA7A protein is significantly increased in postpartum patient tumors and in nulliparous patient tumors that subsequently recurred. Thus, we postulate that SEMA7A is also a general mediator of breast tumor progression. In support of this, our gene expression analysis of multiple human breast cancer datasets reveals that SEMA7A mRNA expression is associated with early recurrence, metastasis, and death. Cumulatively, these data support the hypothesis that SEMA7A promotes tumor progression in breast cancer patients and may be an important therapeutic target. Objective/Hypothesis: A collagen-mediated COX-2/SEMA7A signaling axis is key for invasion, stromal remodeling, and induction of vascular remodeling in the tumor microenvironment, all of which ultimately drive metastasis. Specific Aims: (1) Determine how collagen leads to upregulation of COX-2 and SEMA7A and whether targeting COX-2 in combination with silencing of SEMA7A will block tumor cell invasion. (2) Define the mechanisms by which SEMA7A promotes vascular remodeling and metastasis, determine whether targeting or co-targeting of SEMA7A and COX-2 will block metastasis, and define the relationship between SEMA7A and COX-2 in postpartum breast tumors. Cancer relevance: To establish clinical relevance, we will examine the relationship between SEMA7A and COX-2 protein expression, along with collagen and the vasculature, using multi-color immunostaining and correlate with invasion and recurrence in our postpartum breast cancer patient tissues. The expected outcomes are identification of mechanisms by which COX-2 and SEMA7A support breast tumor progression. Such results could positively impact thousands of breast cancer patients by defining new therapies targeted at the SEMA7A pathway. Given that SEMA7A expression is generally low in adult tissues direct targeting of SEMA7A could have low toxicity.

背景：产后乳腺癌，定义为上次产后 5-10 年内诊断出的乳腺癌分娩后，发生转移并导致死亡的可能性增加两倍以上。这个毁灭性的诊断每年影响数千名年轻女性。我们之前的研究表明，非侵入性乳腺肿瘤与未产小鼠的对照相比，产后小鼠的细胞变得具有侵袭性和转移性。我们还揭示了一种新的反馈循环，涉及胶原介导的 COX-2 上调，从而介导入侵以及产后小鼠的转移。随后的基因表达分析揭示了一个重要且具体的产后乳腺肿瘤细胞中 SEMA7A mRNA 的上调。 SEMA7A 基因编码信号蛋白 7a (Sema7a)，一种信号分子，可驱动神经发育、免疫和组织重塑肺。我们的初步数据表明，SEMA7A 细胞系来源的产后乳腺癌的沉默异种移植物延迟生长、进展为侵袭性癌症，并减少肿瘤中的淋巴管生成微环境。此外，我们还分析了年轻女性乳腺癌队列，结果表明 SEMA7A 蛋白在产后肿瘤患者和未产妇肿瘤患者中显着增加，随后又复发了。因此，我们假设 SEMA7A 也是乳腺肿瘤的一般介质进展。为了支持这一点，我们对多个人类乳腺癌数据集的基因表达分析表明 SEMA7A mRNA 表达与早期复发、转移和死亡相关。累计起来，这些数据支持这样的假设：SEMA7A 促进乳腺癌患者的肿瘤进展，并且可能是一个重要的治疗目标。目标/假设：胶原蛋白介导的 COX-2/SEMA7A 信号轴是侵袭、基质重塑和诱导血管重塑的关键肿瘤微环境，所有这些最终都会驱动转移。具体目标：(1) 确定如何胶原蛋白会导致 COX-2 和 SEMA7A 上调，以及是否针对 COX-2 与 SEMA7A 的沉默将阻止肿瘤细胞的侵袭。 (2) 定义 SEMA7A 推广机制血管重塑和转移，确定 SEMA7A 和 COX-2 是否靶向或共同靶向阻止转移，并定义 SEMA7A 和 COX-2 在产后乳腺肿瘤中的关系。癌症相关性：为了确定临床相关性，我们将检查 SEMA7A 和 COX-2 蛋白表达以及胶原蛋白和脉管系统，使用多色免疫染色和 correlate with invasion and recurrence in our postpartum breast cancer patient tissues. 预期的结果是确定 COX-2 和 SEMA7A 支持乳腺肿瘤进展的机制。这些结果可以通过定义针对乳腺癌的新疗法，对数千名乳腺癌患者产生积极影响。 SEMA7A 途径。鉴于 SEMA7A 表达在成人组织中通常较低，直接靶向 SEMA7A 的毒性较低。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Toward Characterizing Lymphatic Vasculature in the Mammary Gland During Normal Development and Tumor-Associated Remodeling.

DOI：
10.1007/s10911-023-09554-w
发表时间：
2024-01-13
期刊：
Journal of mammary gland biology and neoplasia
影响因子：
2.5
作者：
通讯作者：

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

DOI：
10.1158/0008-5472.can-19-3448
发表时间：
2020-05-01
期刊：
Cancer research
影响因子：
11.2
作者：
Borges VF;Lyons TR;Germain D;Schedin P
通讯作者：
Schedin P

Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival.

产后乳腺癌的进展是由信号蛋白 7a 介导的侵袭和存活驱动的。

DOI：
10.1038/s41388-020-1192-9
发表时间：
2020
期刊：
Oncogene
影响因子：
8
作者：
Tarullo,SarahE;Hill,RyanC;Hansen,KirkC;Behbod,Fariba;Borges,VirginiaF;Nelson,AndrewC;Lyons,TraciR
通讯作者：
Lyons,TraciR