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.

项目概要/摘要 乳腺癌是最常诊断的癌症，也是癌症相关的第二大原因 美国女性死亡人数。超过一半的乳腺癌呈激素受体阳性 (HR+)，这是由于 其雌激素和/或孕激素受体（ER/PR）的表达。虽然 ER 靶向治疗 通常可以成功治疗原发性肿瘤生长，高达 40% 的 ER 阳性肿瘤最终会复发，并且 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 癌症。我们之前的研究发现 Semaphorin 7a (SEMA7A) 是各个方面的调节因子 与 HR+ 乳腺癌进展相关，包括增殖、侵袭和细胞存活。 SEMA7A 是 一种已知可驱动神经元发育、免疫和纤维化的信号分子。 SEMA7A 是一款独特的 信号蛋白家族的成员，因为它是唯一具有可裂解的 GPI 锚的信号蛋白，从而允许 SEMA7A 被释放到细胞外环境中。这支持了我的建议，即 SEMA7A 可能会影响 除了固有的细胞过程之外，肿瘤微环境也是如此。多重宣传分析 乳腺癌患者队列显示，与正常人相比，乳腺肿瘤中 SEMA7A 表达增加 乳腺组织，SEMA7A 表达与生存率下降之间存在显着相关性。采取 总之，这使我推测 SEMA7A 促进乳腺肿瘤进展，并且可能是一种新的 治疗目标。然而，SEMA7A 表达增加背后的分子机制以及如何 SEMA7A 信号导致肿瘤细胞的侵袭性行为仍然未知。 该提案的目标是确定：1​​）SEMA7A 表达在 HR+ 乳腺癌中如何上调， 2) SEMA7A 信号传导如何促进细胞存活，以及 3) SEMA7A 是否通过以下方式促进转移： 血管系统的重塑。在目标1中，我将确定核激素受体是否直接 诱导 SEMA7A 的转录调控。我还将研究 SEMA7A 信号如何诱导观察到的 促生存表型。在目标2中，我将检查SEMA7A是否通过血管促进转移 重塑。这项研究的预期结果将进一步加深我们对 SEMA7A 表达和 HR+ 乳腺癌中的信号传导。这些结果将通过表征新的潜力产生积极影响 HR+乳腺癌的治疗目标。最后，由于 SEMA7A 在大多数成人组织中表达量最低，我们 假设该疗法毒性低，非常适合临床应用。

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