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，经历着显著的结构变化 一个女人的一生。乳腺组织结构是由一群具有自体免疫功能的干细胞维持的。 更新能力，这是组织修复和重塑所必需的。最近，干细胞在乳腺癌中的作用 致癌作用已被认为是转化乳腺癌研究的高度优先事项。干细胞 乳腺癌发生的假设表明，乳腺癌的发生可能与乳腺癌的发生直接相关。 干细胞池的大小及其有丝分裂活性。此外，在乳腺干细胞是唯一的细胞 具有积累所有致癌改变能力的亚群。R 01项目将填补 我们对干细胞在乳腺癌发生中的作用及其与乳腺癌的相互作用的理解存在差距， 癌症风险因素和途径。具体来说，使用前瞻性收集的数据和样本，在护士的 健康研究和护士健康研究II队列，我们将探讨：1）产次的前瞻性关联， 第一胎年龄、出生体重和青少年体型与CD 44、CD 24和ALDH 1A 1干细胞标志物 （n= 1，348）; 2）良性乳腺活检中的干细胞标志物与随后的乳腺癌之间的关联 癌症风险（约190例乳腺癌病例/575例对照）; 3）活检前 循环IGF-1和IGFBP-3（n= 472）与随后良性活检样品中的干细胞标志物。 方法：我们将利用一项偶发性良性乳腺疾病（BBD）研究和一个巢式乳腺癌病例- 在这些队列中进行对照研究，以实现研究目的。所有BBD诊断都是通过 中央病理学评论一些来自良性活检的组织微阵列（TMA）已经在 在项目期间，将增加这些队列和额外的TMA。干细胞标记物将被染色 使用免疫组织化学（IHC）用市售抗体进行染色，并将染色结果 通过自动图像分析进行评估。关于血浆IGF-1和IGFBP-3的信息可从 这些队列中的既往研究。在基线时收集了乳腺癌风险因素数据， 每两年更新一次。意义：我们提出了一个非常新颖的调查，将全面审查 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 在观察到的乳腺癌风险因素与乳腺癌风险之间的关联背后， 这些标志物可以在大部分接受常规治疗的高危女性中提前预测未来的风险。 乳腺活检可以为新型个性化乳腺癌预防和监测铺平道路 战略布局这些结果也将增加IGF途径与表达相关的有限证据。 乳腺干细胞标志物由于干细胞活性可通过多种靶向疗法潜在地改变， 研究结果可以转化为针对乳腺癌风险的干细胞定向药物干预 减少BBD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.