Molecular causes and mechanistic underpinning of breast cancer racial disparity

乳腺癌种族差异的分子原因和机制基础

• 批准号: 9094145
• 负责人: Seema Singh
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094145
• 关键词: African American; Age; Apoptosis; Area; Binding; Binding Proteins; Biological; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Patient; Caucasians; Cell Communication; Cell Line; Cell Proliferation; Cells; Characteristics; Clinical; Data; Deletion Mutation; Disease; Disease Outcome; Down-Regulation; Drug Targeting; Growth; Infiltration; Inflammatory; Interleukin 6 Receptor; Interleukin-6; Intervention; Lead; Link; Luciferases; MDA MB 231; MDA-MB-468; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maps; Measures; Mediating; Mediator of activation protein; MicroRNAs; Molecular; Molecular Profiling; Monitor; Mutation Analysis; Neoplasm Metastasis; Nude Mice; Outcome; Pathway interactions; Patients; Perception; Phenotype; Phosphorylation; Play; Production; Public Health; RNA Interference; Race; Recurrence; Regulatory Element; Reporter; Research; Resistance; Risk; Role; STAT3 gene; Sampling; Serum; Site; Staging; Testing; Tissues; Tumor Biology; United States; Untranslated Regions; Up-Regulation; Woman; Xenograft procedure; aggressive therapy; base; breast cancer diagnosis; breast density; cancer health disparity; caucasian American; clinically relevant; cytokine; density; epithelial to mesenchymal transition; experience; high risk; in vivo imaging; insight; knock-down; macrophage; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; outcome forecast; overexpression; potential biomarker; promoter; public health relevance; racial difference; racial disparity; receptor; research study; resistin; response; stemness; therapy resistant; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): African American (AA) women are more likely to have aggressive breast cancer (BC) and experience greater mortality rates as compared to Caucasian (CA) women. Another upsetting fact is that this cancer outcome gap has continued to widen over past several years underscoring the immediate need to make progress in this area. It is being increasingly appreciated that tumor microenvironment (TME) may play an important role in BC racial disparity; however, underlying molecular and mechanistic basis is not clearly understood. This project is built upon our novel findings suggesting the existence of a TME-tumor cell interaction-driven regulatory loop, which is predominantly active in AA patients. We demonstrate that 1) serum levels of inflammatory cytokines, resistin and IL6, are significantly elevated in AA BC patients compared to their CA counterparts, 2) AA BCs have significantly greater expression and phosphorylation of STAT3 compared to CA BCs, 3) treatment of triple-negative breast cancer (TNBC) cell lines from both AA and CA patients with resistin promotes expression of STAT3/pSTAT3 and enhances IL6 production, thus suggesting a dominant role of differential TME in overall disease outcome, 4) IL6 mediates the effect of resistin on STAT3 phosphorylation, 5) resistin promotes aggressive tumor phenotypes and therapy-resistance in BC cells through STAT3 induction, 6) resistin also upregulates LIN28A, a regulator of stemness, and downregulates let-7 miRNA, and 7) LIN28A silencing abrogates resistin-induced upregulation of IL6, pSTAT3 and STAT3. Based on these findings, we hypothesize that intrinsic differences in tumor biology contributes to BC racial disparity and resistin-LIN28A-(IL6)- STAT3/pSTAT3 serves as an important regulatory loop controlling the aggressive and therapy-resistant phenotypes of BC cells. This hypothesis will be tested in three specific aims. In aim 1, we will characterize the molecular mechanisms underlying resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop by examining the pathways regulating resistin-induced LIN28A expression, and whether LIN28A mediates resistin-induced let-7 downregulation, which then leads to STAT3 and IL6 upregulation in BC cells. In aim 2, we will examine the functional significance of this regulatory by using luciferase-tagged, control or LIN28A-/STAT3-silenced BC cell lines and characterize the response of resistin and its downstream effectors on growth, metastasis and therapy-resistance in an orthotopic nude mice model. In aim 3, we will determine the clinical relevance of the components of resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop in BC racial disparity by examining their expression in clinical samples and assessing their correlation (alone and in combination) with TME and tumor cell characteristics as well as with race and patient's survival. Together, these studies will provide novel insight into molecular causes and mechanistic underpinning of BC racial disparity and provide novel set of biomarkers and potential drug-targets to develop novel ways for reducing the widening gaps in clinical outcome of AA and CA BC patients.

 描述（由申请人提供）：与白人（CA）女性相比，非洲裔美国人（AA）女性更可能患有侵袭性乳腺癌（BC），并且死亡率更高。另一个令人不安的事实是，这种癌症结果的差距在过去几年中继续扩大，这突出了在这一领域取得进展的迫切需要。越来越多的人认识到肿瘤微环境（TME）可能在BC种族差异中发挥重要作用;然而，潜在的分子和机制基础尚不清楚。该项目是建立在我们的新发现的基础上的，该发现表明存在TME-肿瘤细胞相互作用驱动的调节环，该调节环主要在AA患者中活跃。我们证明了1）与CA对应物相比，AA BC患者中炎性细胞因子、IL 1 n和IL 6的血清水平显著升高，2）与CA BC相比，AA BC具有显著更高的STAT 3表达和磷酸化，3）用Alcohol n处理来自AA和CA患者的三阴性乳腺癌（TNBC）细胞系促进STAT 3/STAT 4的表达。pSTAT 3和增强IL 6的产生，从而表明在总体疾病结果中差异性TME的主导作用，4）IL 6介导Bp 2n对STAT 3磷酸化的作用，5）Bp 2n通过STAT 3诱导促进BC细胞中的侵袭性肿瘤表型和治疗抗性，6）Bp 2n还上调LIN 28 A，一种干性调节剂，并且下调let-7 miRNA，和7）LIN 28 A沉默消除抵抗素诱导的IL 6、pSTAT 3和STAT 3的上调。基于这些发现，我们假设肿瘤生物学的内在差异导致BC种族差异，并且抵抗素-LIN 28 A-（IL 6）-STAT 3/pSTAT 3作为控制BC细胞的侵袭性和治疗抗性表型的重要调节环。这一假设将在三个具体目标中得到检验。在目标1中，我们将通过检查调节抵抗素诱导的LIN 28 A表达的途径来表征抵抗素-LIN 28 A-（IL 6）-STAT 3/pSTAT 3调节环的分子机制，以及LIN 28 A是否介导抵抗素诱导的let-7下调，然后导致BC细胞中STAT 3和IL 6上调。在目标2中，我们将通过使用标记有端粒酶的对照或LIN 28 A-/STAT 3-沉默的BC细胞系来检查这种调节的功能意义，并在原位裸小鼠模型中表征Bcln及其下游效应物对生长、转移和治疗抗性的响应。在目标3中，我们将通过检查抵抗素-LIN 28 A-（IL 6）-STAT 3/pSTAT 3调节环的组分在临床样品中的表达并评估其与TME和肿瘤细胞特征以及与种族和患者存活的相关性（单独和组合）来确定它们在BC种族差异中的临床相关性。总之，这些研究将为BC种族差异的分子原因和机制基础提供新的见解，并提供一组新的生物标志物和潜在的药物靶点，以开发新的方法来减少AA和CA BC患者临床结局的差距。