Hormonal Regulation and Tumor Promotional Phenotypes of Semaphorin 7a in Breast Cancer

乳腺癌中信号蛋白 7a 的激素调节和肿瘤促进表型

• 批准号: 10062905
• 负责人: Lyndsey S Crump
• 金额: $ 2.55万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-06 至 2021-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062905
• 关键词: Adult; Affect; Apoptosis; Binding; Binding Sites; Blood; Blood Vessels; Bone Marrow; Brain; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast cancer metastasis; CASP3 gene; Cancer Etiology; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cessation of life; Cleaved cell; Cornea; Data; Data Set; Development; Disease; Environment; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exhibits; Family; Fibrosis; Fulvestrant; Gene Expression Profiling; Genetic Transcription; Goals; Hormones; Human; Immunity; In Vitro; Knockout Mice; Ligands; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediator of activation protein; Messenger RNA; Mifepristone; Modeling; Molecular; Molecular Target; Mus; Mutation; Neoplasm Metastasis; Neurons; Nuclear Hormone Receptors; Outcomes Research; PI3K/AKT; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Pregnancy; Primary Neoplasm; Progesterone; Progesterone Receptors; Prognosis; Proto-Oncogene Proteins c-akt; Puberty; Pulmonary Fibrosis; Recurrence; Regulation; Research; Role; Semaphorins; Signal Transduction; Signaling Molecule; Signaling Protein; Techniques; Testing; Tissues; Toxic effect; Transcriptional Regulation; United States; Up-Regulation; Vascular remodeling; Woman; axon guidance; breast cancer progression; cancer diagnosis; cell behavior; clinical application; cohort; density; experimental study; extracellular; hormone receptor-positive; hormone regulation; human tissue; investigator training; malignant breast neoplasm; mammary; mammary epithelium; member; migration; neoplastic cell; neuron development; new therapeutic target; novel; programs; promoter; response; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

Project Summary/Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-associated death in women in the United States. Over half of all breast cancers are hormone receptor positive (HR+), due to their expression of the estrogen and/or progesterone receptor (ER/PR). While ER-targeted therapies are typically successful at treating primary tumor growth, up to 40% of ER-positive tumors eventually recur and metastasize. Therefore, novel molecular targets are needed to treat recurrent and metastatic HR+ breast cancers. Our previous research identified Semaphorin 7a (SEMA7A) as a mediator of various aspects associated with HR+ breast cancer progression, including proliferation, invasion, and cell survival. SEMA7A is a signaling molecule known to drive neuronal development, immunity, and fibrosis. SEMA7A is a unique member of the semaphorin family, as it is the only semaphorin with a GPI-anchor that can be cleaved, allowing SEMA7A to be shed into the extracellular environment. This supports my proposal that SEMA7A may affect the tumor microenvironment in addition to inherent cellular processes. Analysis of multiple publicity available breast cancer patient cohorts revealed increased SEMA7A expression in breast tumors compared to normal breast tissue, as well as a significant correlation between SEMA7A expression and decreased survival. Taken together, this led me to hypothesize that SEMA7A promotes breast tumor progression and may be a novel therapeutic target. However, the molecular mechanisms behind increased SEMA7A expression and how SEMA7A signals to result in aggressive tumor cell behaviors remain unknown. The goals of this proposal are to determine: 1) how SEMA7A expression is upregulated in HR+ breast cancer, 2) how SEMA7A signaling promotes cell survival, and 3) whether SEMA7A promotes metastasis via remodeling of the blood vasculature. In aim 1, I will determine whether nuclear hormone receptors directly induce transcriptional regulation of SEMA7A. I will also examine how SEMA7A signals to induce the observed pro-survival phenotype. In aim 2, I will examine if SEMA7A promotes metastasis through blood vessel remodeling. The expected outcomes of this research will further our understanding of SEMA7A expression and signaling in HR+ breast cancer. These results will have a positive impact by characterizing a novel potential therapeutic target in HR+ breast cancer. Finally, as SEMA7A is minimally expressed in most adult tissues, we postulate this therapy will have low toxicity, making it ideal for clinical application.

项目总结/摘要 乳腺癌是最常见的癌症，也是癌症相关疾病的第二大原因。 美国女性的死亡率。超过一半的乳腺癌是激素受体阳性（HR+）， 雌激素和/或孕激素受体（ER/PR）的表达。虽然ER靶向治疗是 通常成功治疗原发性肿瘤生长，高达40%的ER阳性肿瘤最终复发， 转移因此，需要新的分子靶点来治疗复发性和转移性HR+乳腺癌 癌的我们前期的研究发现Semaphorin 7a（SEMA 7A）是一个多方面的中介因子 与HR+乳腺癌进展相关，包括增殖、侵袭和细胞存活。SEMA 7A是 一种已知的驱动神经元发育、免疫和纤维化的信号分子。SEMA 7A是一种独特的 它是脑信号蛋白家族的成员，因为它是唯一可以被切割的具有GPI锚的脑信号蛋白， SEMA 7A将脱落到细胞外环境中。这支持了我的建议，即SEMA 7A可能会影响 除了固有的细胞过程之外，还包括肿瘤微环境。对现有多种宣传的分析 乳腺癌患者队列显示，与正常对照组相比，乳腺肿瘤中SEMA 7A表达增加 乳腺组织，以及SEMA 7A表达和生存率下降之间的显著相关性。采取 总之，这使我假设SEMA 7A促进乳腺肿瘤进展，可能是一种新的 治疗靶点然而，SEMA 7A表达增加背后的分子机制以及如何增加SEMA 7A的表达， SEMA 7A信号导致侵袭性肿瘤细胞行为仍然未知。 该提案的目标是确定：1）SEMA 7A表达如何在HR+乳腺癌中上调， 2)SEMA 7A信号传导如何促进细胞存活，以及3）SEMA 7A是否通过 重塑血管系统在目标1中，我将确定核激素受体是否直接 诱导SEMA 7A转录调节。我还将研究SEMA 7A信号如何诱导观察到的 促存活表型。在目的2中，我将检查SEMA 7A是否促进通过血管的转移 重塑本研究的预期结果将进一步加深我们对SEMA 7A表达的理解， HR+乳腺癌中的信号传导。这些结果将产生积极的影响，通过表征一个新的潜力， HR+乳腺癌的治疗靶点。最后，由于SEMA 7A在大多数成人组织中表达最低，我们 假设这种疗法具有低毒性，使其成为临床应用的理想选择。

项目成果

Cross-talk between SIM2s and NFκB regulates cyclooxygenase 2 expression in breast cancer.

SIM2 和 NFκB 之间的串扰调节乳腺癌中环氧合酶 2 的表达。

• DOI: 10.1186/s13058-019-1224-y
• 发表时间: 2019
• 期刊: Breast cancer research : BCR
• 作者: Wyatt,GarhettL;Crump,LyndseyS;Young,ChloeM;Wessells,VeronicaM;McQueen,ColeM;Wall,StevenW;Gustafson,TanyaL;Fan,Yang-Yi;Chapkin,RobertS;Porter,WestonW;Lyons,TraciR
• 通讯作者: Lyons,TraciR

Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms.

• DOI: 10.20517/2394-4722.2019.01
• 发表时间: 2019-01-01
• 期刊: Journal of cancer metastasis and treatment
• 作者: Wallace, Taylor R;Tarullo, Sarah E;Lyons, Traci R
• 通讯作者: Lyons, Traci R