Stromal contributions to breast carcinogenesis

基质对乳腺癌发生的贡献

• 批准号: 10748124
• 负责人: Rulla M Tamimi
• 金额: $ 75.85万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748124
• 关键词: Address; Age; Age at Menarche; Architecture; Area; Benign; Biometry; Biopsy; Biopsy Specimen; Birth; Breast; Breast Cancer Epidemiology; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Carcinogenesis; Breast Diseases; Breast Feeding; Breast biopsy; Cancer Biology; Cancer Etiology; Cancer Patient; Characteristics; Clinical Management; Collaborations; Complex; Data; Data Collection; Development; Epithelium; Extracellular Matrix; Fibroblasts; First Births; Future; General Population; High Risk Woman; Histopathologic Grade; Human; Image Analysis; Intervention; Investigation; Knowledge; Life; Link; MMP14 gene; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammographic Density; Mammography; Metastatic Neoplasm to Lymph Nodes; Methodology; Molecular; Molecular Profiling; Nested Case-Control Study; Nulliparity; Nurses' Health Study; Organ; Outcome; Pharmacologic Substance; Play; Population Study; Prevention strategy; Primary Prevention; Process; Productivity; Proliferating; Prospective cohort; Public Health; Recording of previous events; Reproductive History; Resources; Risk; Risk Factors; Risk Management; Risk Reduction; Role; Sampling; Signal Transduction; Stromal Cells; Structure; Tenascin; Tissues; Translating; Universities; Variant; Washington; Woman; Women' s Health; automated image analysis; biomarker identification; breast density; breast pathology; carcinogenesis; case control; cohort; density; design; differential expression; epidemiology study; follow-up; improved; individualized prevention; malignant breast neoplasm; mammary; mammary epithelium; novel; parity; parous; patient population; predictive marker; prospective; repository; reproductive; risk prediction; stem cell biomarkers; stem cells; surveillance strategy; targeted treatment; tissue repair; tissue resource; tumor; tumor initiation

ABSTRACT The human breast is a highly organized, complex organ that consists of an epithelial tissue surrounded by stroma that regulates its proliferation, differentiation, and survival. Stroma is responsible for sustaining normal breast tissue structure and function via a variety of signaling mechanisms that control and regulate normal processes and suppress malignant transformation. The role of stroma in breast tumor initiation, progression, and responsiveness to treatment as well as potential utility for targeted therapies has been widely discussed in recent reviews. While cancer tissue stroma has been widely explored, the evidence of stromal contributions to early stages of carcinogenesis is extremely limited. To fill these gaps, we propose a conceptually and methodologically novel investigation that will focus on benign breast disease (BBD) and high mammographic breast density (MBD), strong risk factors both independently associated with increased breast cancer (BCa) risk, which presents a unique opportunity for studying early changes in the breast and elucidating underlying molecular mechanisms. The study will be conducted by an interdisciplinary team of experts in BCa epidemiology, breast pathology/image analysis, BCa biology, and biostatistics, with a history of long and productive collaboration. We will use data and breast biopsy samples from three established prospective cohorts (Nurses’ Health Study, Nurses’ Health Study II, and Women’s Health Repository) to address the following aims: (1) prospectively examine associations of reproductive risk factors (e.g., parity, age at first birth) with expression of stromal markers (αSMA, FAP, MMP14, TNC, and S100A6) in benign biopsy samples from cancer-free women (n~1,350); (2) examine associations of stromal markers with MBD (n~1,350); and (3) examine associations of stromal markers in women with a previous benign biopsy and the risk of subsequent BCa in a nested case-control design (~400 cases/~975 controls). This proposal leverages established tissue resources, use of validated multiplex immunoflourence for stromal markers, and automated image analysis for MBD assessment. Understanding the associations of BCa risk factors with stromal markers will advance our knowledge on its role in breast carcinogenesis in epidemiologic studies. We will generate the first comprehensive data on the stromal markers’ expression in non-cancer breast and will identify markers that could significantly advance future risk prediction. Stromal activity is potentially modifiable via a variety of targeted therapies; if our project successfully demonstrates an association between stromal markers in benign breast tissue and increased BCa risk and/or high MBD, these findings could eventually translate into pharmaceutical interventions aimed at primary BCa prevention in high-risk women with high MBD and/or BBD. Importantly, these findings would apply to a large segment of women undergoing routine biopsies and those with high MBD in whom novel prevention strategies, improved risk prediction, and tailored clinical management are urgently needed.

抽象的 人乳房是一个高度组织的，复杂的器官，由周围的上皮组织组成 调节其增殖，分化和生存的基质。基质负责正常 乳房组织结构和功能通过控制和调节正常的多种信号传导机制 过程并抑制恶性转化。基质在乳腺肿瘤开始，进展中的作用， 以及对治疗的反应以及针对目标疗法的潜在效用已广泛讨论 最近的评论。虽然广泛探索了癌组织基质，但基质贡献的证据 癌变的早期阶段极为有限。为了填补这些空白，我们在概念上提出了一个， 方法论上的新型研究将重点放在良性乳房疾病（BBD）和高乳房X线摄影 乳房密度（MBD），强烈的危险因素都与乳腺癌增加（BCA）独立相关 风险，这为研究乳房的早期变化和阐明潜在的风险提供了独特的机会 分子机制。该研究将由BCA的跨学科专家团队进行 流行病学，乳房病理/图像分析，BCA生物学和生物统计学，具有悠久的历史 富有成效的合作。我们将使用三个已建立的预期的数据和乳房活检样本 队列（护士健康研究，护士健康研究II和妇女健康存储库），以解决 以下目的：（1）前瞻性检查生殖危险因素的关联（例如，均等，初生年龄） 从良性活检样品中的基质标记（αSMA，FAP，MMP14，TNC和S100A6）的表达 无癌女性（n〜1,350）； （2）基质标记与MBD的检查协会（n〜1,350）； （3） 检查先前有良性活检的女性中基质标记的关联以及随后的风险 BCA在嵌套的病例对照设计中（〜400个案例/〜975个对照）。该建议利用已建立的组织 资源，使用经过验证的多重免疫流量用于基质标记，以及用于自动化图像分析 MBD评估。了解BCA风险因素与基质标记的关联将推动我们的 了解其在流行病学研究中在乳腺癌发生中的作用。我们将生成第一个 关于基质标记在非癌症乳房表达的全面数据，并将确定标记 可以大大提高未来的风险预测。基质活性可能通过多种 靶向疗法；如果我们的项目成功证明了良性中基质标记之间的关联 乳腺组织并增加了BCA风险和/或高MBD，这些发现最终可能转化为 针对高MBD和/或BBD的高风险女性，旨在预防初级BCA的药物干预措施。 重要的是，这些发现将适用于大部分经历常规活检的妇女 具有高MBD的新型预防策略，改善风险预测和量身定制的临床管理 迫切需要。