Stromal contributions to breast carcinogenesis

摘要 人类的乳房是一个高度有组织的复杂器官，由被 调节其增殖、分化和存活的基质。基质负责维持正常 乳房组织结构和功能通过各种信号机制控制和调节正常 处理和抑制恶变。间质在乳腺肿瘤发生、发展、发展中的作用 对治疗的反应性以及靶向治疗的潜在效用已在 最近的评论。虽然癌症组织间质已经被广泛探索，但有证据表明间质对 癌症发生的早期阶段极其有限。为了填补这些空白，我们提出了一个概念上的和 方法上的新研究，将重点放在良性乳腺疾病(BBD)和高级乳房X光检查 乳房密度(MBD)，与乳腺癌(BCA)增加独立相关的强烈危险因素 风险，这为研究乳房早期变化和阐明潜在原因提供了一个独特的机会 分子机制。这项研究将由BCA的一个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，具有悠久的历史和 富有成效的协作。我们将使用来自三个已确定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和妇女健康资料库)，以解决 以下目标：(1)前瞻性地检查生殖危险因素(例如，产次、初次生育年龄)之间的关系 α、FAP、MMP14、TnC和S100A6等间质标志物在良性卵巢癌组织中的表达 无癌女性(n~1350)；(2)检查基质标记物与MBD的相关性(n~1350)；以及(3) 检查女性间质标志物与先前的良性活检和随后的风险之间的关系 BCA采用嵌套病例对照设计(~400例/~975例对照)。这项提议利用已建立的组织 资源，对基质标记使用经过验证的多重免疫繁荣，以及自动图像分析 MBD评估。了解BCA危险因素与基质标记物的关系将促进我们的 在流行病学研究中对其在乳腺癌发生中作用的认识。我们将生成第一个 关于间质标记物在非癌症乳腺中表达的全面数据，并将确定 可以显著提高对未来风险的预测。间质活动可能通过多种途径改变 靶向治疗；如果我们的项目成功地证明了良性间质标记物之间的关联 乳房组织和增加的BCA风险和/或高MBD，这些发现最终可能转化为 药物干预旨在对患有高MBD和/或BBD的高危妇女进行BCA的初级预防。 重要的是，这些发现将适用于大部分接受常规活组织检查的女性和那些 具有高MBD的患者中，新的预防策略、改进的风险预测和量身定制的临床管理 都是迫切需要的。

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.