Stromal contributions to breast carcinogenesis

摘要 人类乳房是一个高度组织化的复杂器官，由上皮组织组成， 调节其增殖、分化和存活的基质。基质负责维持正常的 乳腺组织结构和功能通过各种信号机制，控制和调节正常的 处理和抑制恶性转化。间质在乳腺肿瘤发生、发展 和对治疗的反应以及靶向治疗的潜在效用已经在 最近的评论虽然癌组织间质已被广泛探索，但间质对肿瘤的作用的证据仍然存在。 早期阶段的致癌作用非常有限。为了填补这些空白，我们提出了一个概念和 方法学上的新研究，将重点关注良性乳腺疾病（BBD）和高乳腺X线摄影 乳腺密度（MBD），与乳腺癌（BCa）增加独立相关的强风险因素 风险，这为研究乳房的早期变化和阐明潜在的 分子机制该研究将由BCa的跨学科专家团队进行 流行病学，乳腺病理学/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。我们将使用来自三个已建立的前瞻性研究的数据和乳腺活检样本， 队列（护士健康研究，护士健康研究II和妇女健康知识库），以解决 以下目的：（1）前瞻性地检查生殖风险因素的关联（例如，产次、初次生育年龄） 在良性活检样本中表达间质标记物（αSMA、FAP、MMP 14、TNC和S100 A6）， 无癌女性（n~ 1，350）;（2）检查间质标记物与MBD的相关性（n~ 1，350）;（3） 检查妇女间质标记物与既往良性活检的关系， 巢式病例对照设计中的BCa（约400例病例/约975例对照）。这项提案利用了现有的组织 资源，使用经验证的多重免疫荧光进行基质标记，并进行自动图像分析， MBD评估了解BCa危险因素与间质标志物的关系将促进我们的研究。 在流行病学研究中了解其在乳腺癌发生中的作用。我们将生成第一个 关于非癌乳腺中基质标志物表达的综合数据，并将鉴定 可以大大提高未来的风险预测。基质活性可通过多种途径进行潜在的改变， 靶向治疗;如果我们的项目成功地证明了良性肿瘤中基质标记物之间的关联， 乳腺组织和增加的BCa风险和/或高MBD，这些发现最终可能转化为 药物干预，旨在对高MBD和/或BBD的高危女性进行BCa初级预防。 重要的是，这些发现将适用于大部分接受常规活检的妇女， 新的预防策略，改善的风险预测和定制的临床管理 是迫切需要的。

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.