Minimal Residual Disease and Mechanisms of Breast Cancer Recurrence

描述（由申请人提供）：人类癌症的一个主要特征是在原发性肿瘤明显成功治疗后，残留的肿瘤细胞（称为微小残留病）在假定的静止状态下存活和持续存在。最终，这些细胞可能会从休眠状态重新出现并恢复生长，导致癌症复发。例如，约30%缺乏任何转移的临床或组织病理学迹象的乳腺癌患者在其骨髓中存在播散性肿瘤细胞。这些残留的肿瘤细胞构成了肿瘤复发的细胞库。由于复发性乳腺癌通常是一种不治之症，乳腺癌细胞在休眠状态下存活和复发的倾向是临床结果的最重要决定因素。尽管乳腺癌进展的这些方面具有无与伦比的临床重要性，但是，对微小残留病，肿瘤休眠和复发的生物学或机制知之甚少。因此，了解残留肿瘤细胞的生物学并阐明有助于肿瘤休眠和复发的分子途径和细胞过程是癌症研究的关键优先事项。这是这个应用程序的重点。 研究乳腺癌微小残留病、肿瘤休眠和复发的一个特别困难是识别和分离患者体内残留的肿瘤细胞的挑战，以及缺乏重现乳腺癌进展这些关键特征的动物模型。为了解决这一关键差距，我们已经开发并验证了一系列多西环素诱导的转基因小鼠模型，用于MYC，HER 2/neu，Wnt 1和Akt过表达乳腺癌，这些乳腺癌显示出人类乳腺癌进展的关键特征，包括微小残留疾病，肿瘤休眠和复发。 本申请将采用一组独特的条件性转基因小鼠模型，以解决有关残留肿瘤细胞的生物学特性以及导致肿瘤休眠和复发的途径的基本问题。本申请的具体目的是：1.确定肿瘤起始细胞对残留肿瘤性疾病的贡献;以及2.确定par-4、Ssb-1和NF-kB通路在肿瘤休眠和复发中的作用。第一个目标是检验肿瘤消退后残留在乳腺中的肿瘤细胞富含癌症干细胞的假设。第二个目的将使用原位和完整复发模型来确定par-4下调和Ssb-1上调对乳腺肿瘤复发的功能贡献，以及NF-κ B途径活化在该过程中所起的作用。来自新辅助治疗试验的配对患者样本将用于验证更多研究的临床相关性。最终，了解残留肿瘤细胞的生物学，以及肿瘤休眠和复发的机制，应该加速开发更有效的方法来检测和根除休眠的肿瘤细胞和预防乳腺癌复发。 公共卫生相关性：罕见乳腺癌细胞在治疗后以休眠状态存活的能力是临床结果的最重要决定因素，因为由残留肿瘤细胞引起的复发性乳腺癌通常是不可治愈的。因此，了解残留肿瘤细胞的生物学并阐明有助于肿瘤休眠和复发的分子途径和细胞过程是癌症研究的关键优先事项。通过确定乳腺癌复发的途径，这种应用可以促进更有效的治疗方法的发展，以消除休眠的肿瘤细胞和预防乳腺癌复发。

DESCRIPTION (provided by applicant): A cardinal feature of human cancers is the survival and persistence of residual neoplastic cells - referred to as minimal residual disease - in a presumed quiescent state following the apparently successful treatment of the primary tumor. Ultimately, these cells may re-emerge from their dormant state and resume growth, leading to cancer recurrence. For example, ~30% of breast cancer patients lacking any clinical or histopathological signs of metastasis have disseminated tumor cells present in their bone marrow. These residual neoplastic cells constitute the cellular reservoir from which tumor recurrences invariably arise. Since recurrent breast cancer is typically an incurable disease, the propensity of breast cancer cells to survive in a dormant state and recur is the most important determinant of clinical outcome. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, little is known about the biology or mechanisms of minimal residual disease, tumor dormancy, and recurrence. Accordingly, understanding the biology of residual tumor cells and elucidating the molecular pathways and cellular processes that contribute to tumor dormancy and recurrence is a critical priority in cancer research. This is the focus of this application. A particular difficulty in studying minimal residual disease, tumor dormancy, and recurrence in breast cancer has been the challenge of identifying and isolating residual neoplastic cells in patients, and the lack of animal models that recapitulate these key features of breast cancer progression. To address this critical gap, we have developed and validated a series of doxycycline-inducible transgenic mouse models for MYC, HER2/neu, Wnt1, and Akt-overexpressing breast cancers that display key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. This application will employ a unique set of conditional transgenic mouse models to address fundamental questions regarding the biological properties of residual tumor cells and the pathways that contribute to tumor dormancy and recurrence. The specific aims of this application are to: 1. Determine the contribution of tumor initiating cells to residual neoplastic disease; and 2. Determine the role of par-4, Ssb-1, and the NF-kB pathway in tumor dormancy and recurrence. The first aim will test the hypothesis that residual neoplastic cells that persist in the mammary gland following tumor regression are enriched for cancer stem cells. The second aim will use orthotopic and intact recurrence models to determine the functional contribution of par-4 down- regulation and Ssb-1 up-regulation to mammary tumor recurrence, and the role played by NF-kB pathway activation in this process. Paired patient samples from a neoadjuvant trial will be used to validate the clinical relevance of more studies. Ultimately, understanding the biology of residual neoplastic cells, as well as the mechanisms of tumor dormancy and recurrence, should accelerate the development of more effective approaches to detecting and eradicating dormant tumor cells and preventing breast cancer recurrence. PUBLIC HEALTH RELEVANCE: The ability of rare breast cancer cells to survive in a dormant state following therapy is the most important determinant of clinical outcome, since recurrent breast cancers that arise from residual tumor cells are typically incurable. Accordingly, understanding the biology of residual tumor cells and elucidating the molecular pathways and cellular processes that contribute to tumor dormancy and recurrence is a critical priority in cancer research. By identifying the pathways by which breast cancers recur, this application could facilitate the development of more effective therapeutic approaches to eliminate dormant tumor cells and prevent breast cancer recurrence.