The role of breast stem cells in breast cancer etiology and risk prediction

背景和目的：乳腺组织是动态的，并经历着显著的结构变化 在女人的一生中。乳腺组织结构由一群干细胞维持，这些干细胞具有自我- 对组织修复和重塑至关重要的更新能力。最近，干细胞在乳房中的作用 癌变已经被认为是转化型乳腺癌研究的一个高度优先事项。干细胞 乳腺癌发生假说表明，乳腺癌的发生可能与 干细胞库的大小及其有丝分裂活性。此外，在乳腺中，干细胞是唯一的细胞 有能力累积所有致癌改变的亚群。拟议的R01项目将填补 干细胞在乳腺癌发生中的作用及其与乳腺的相互作用认识上的差距 癌症危险因素和途径。具体地说，使用前瞻性收集的数据和样本 健康研究和护士健康研究II队列，我们将探索：1)产次的前瞻性关联， CD44、CD24和ALDH1A1干细胞标记物对初次出生年龄、出生体重和青少年体型的影响 (n=1,348)；2)良性乳腺活检中干细胞标志物与随后的乳腺之间的关系 癌症风险(约190例乳腺癌病例/575例对照)；以及3)活检前的前瞻性关联 在随后的良性活检样本中检测循环中的IGF-1和IGFBP-3(n=472)和干细胞标志物。 方法：我们将利用一例良性乳腺疾病(BBD)事件研究和一例嵌套性乳腺癌病例- 在这些队列中进行对照研究，以达到研究目的。所有的BBD诊断都是通过 中央病理学回顾。一些来自良性活检的组织微阵列(TMA)已经在 这些队列和额外的TMA将在项目期间增加。干细胞标记物将被染色 与商用抗体使用免疫组织化学(IHC)，染色结果将是 通过自动图像分析进行评估。有关血浆IGF-1和IGFBP-3的信息，请访问 之前在这些队列中进行的研究。乳腺癌风险因素数据已在基线和 每两年更新一次。意义：我们提出了一项非常新颖的调查，将全面检查 干细胞标记物在乳腺癌发生中的作用。这项研究旨在阐明分子途径 在观察到的乳腺癌危险因素与乳腺癌风险之间的关联背后，以及确定 在大部分接受常规治疗的高危女性中，可以提高未来风险预测的标志物 乳腺活检为新的个性化乳腺癌预防和监测铺平了道路 战略。这一结果也将增加关于IGF途径与表达之间联系的有限证据 乳房干细胞标志物。由于干细胞的活性可能会通过各种靶向治疗而改变，因此 这些发现可能转化为针对乳腺癌风险的干细胞导向药物干预 减少患有BBD的高危妇女，迫切需要新的预防策略。

Background and Objectives: Breast tissue is dynamic and undergoes significant structural changes throughout a woman's life. The breast tissue architecture is maintained by a population of stem cells with self- renewal capacity which are essential for tissue repair and remodeling. Recently, the role of stem cells in breast carcinogenesis has been recognized as a high priority for translational breast cancer research. The stem cell hypothesis of breast carcinogenesis suggests that breast cancer development might be directly related to the size of the stem cell pool and its mitotic activity. Further, in the mammary gland stem cells are the only cell subpopulation that has capacity to accumulate all the oncogenic alterations. The proposed R01 project will fill the gaps in our understanding of the role of stem cells in breast carcinogenesis and their interplay with breast cancer risk factors and pathways. Specifically, using prospectively collected data and samples within Nurses' Health Study and Nurses' Health Study II cohorts, we will explore: 1) the prospective associations of parity, age at first birth, birthweight, and adolescent body size with CD44, CD24, and ALDH1A1 stem cell markers (n=1,348); 2) the association between stem cell markers in benign breast biopsies and subsequent breast cancer risk (~190 breast cancer cases/575 controls); and 3) the prospective associations of pre-biopsy circulating IGF-1 and IGFBP-3 (n= 472) with stem cell markers in subsequent benign biopsy samples. Methods: We will utilize an incident benign breast disease (BBD) study and a nested breast cancer case- control study within these cohorts to address the study aims. All BBD diagnoses are being confirmed with central pathology review. Some tissue microarrays (TMAs) from benign biopsies have been constructed in these cohorts, and additional TMAs will be added during the project period. Stem cell markers will be stained with commercially available antibodies using immunohistochemistry (IHC), and the staining results will be evaluated with automated image analysis. Information on plasma IGF-1 and IGFBP-3 is available from previous studies within these cohorts. Breast cancer risk factor data have been collected at baseline and updated biennially. Significance: We propose a highly novel investigation that will comprehensively examine the role of stem cell markers in breast carcinogenesis. The study aims to shed light on molecular pathways behind the observed associations of breast cancer risk factors with breast cancer risk as well as to identify markers that could advance future risk prediction in a large segment of high-risk women undergoing routine breast biopsies which could pave the way for novel personalized breast cancer prevention and surveillance strategies. The results will also add to the limited evidence on the association of IGF pathway with expression of breast stem cell markers. As stem cell activity is potentially modifiable via a variety of targeted therapies, the findings could translate into stem cell-directed pharmaceutical interventions aimed at breast cancer risk reduction in high-risk women with BBD in whom novel prevention strategies are urgently needed.