Does stanniocalcin predict late breast cancer recurrence, or is it a fish story?

项目摘要/摘要 乳腺癌筛查和治疗的有效性的进步减少了乳房 过去几十年的癌症死亡率。这些进步来自避免复发，但也来自 延迟性复发。化疗、内分泌治疗和放射治疗的成功通常是 以乳腺癌确诊后头五年复发风险的降低来衡量。许多 然而，复发发生的时间较晚，也就是说，在确诊后五年以上。这些复发是从 单个休眠细胞或肿瘤细胞死亡平衡了肿瘤细胞生长的微转移。多么 一个细胞或一小群细胞能在恶劣的微环境中存活五年以上吗？ 至少在一开始，通常包括癌症治疗引起的低氧环境？ 一种可能的解释是，能够吸收锡钙素的肿瘤更有可能存活下来。 在这种情况下，并在确诊后五年或更长时间内复发。史坦尼卡素是一种荷尔蒙，首次在 硬骨鱼，在那里它调节鳃中钙的浓度。在人类中，神经细胞、脂肪细胞、心脏 细胞、卵子和其他长寿细胞在面临低氧压力时，会招募锡钙素作为生存策略， 帮助它们在有时恶劣的条件下生活，方法是将质子运输从糖基化中分离出来 线粒体。初步的人体证据和体外研究表明，锡钙素的肿瘤表达是一种 复发风险的标志，尤其是晚期复发风险。因此，我们建议使用现有的 来自约1700名乳腺癌患者(841名复发患者和841名匹配对照)的生物库与完整 临床资料和对复发的长期随访，以调查锡钙素的表达是否具有特异性 晚期复发风险的标记。我们将确定晚期复发的乳腺癌患者是否 与早期乳腺癌患者相比，乳腺癌患者更有可能患有表达锡钙素的原发肿瘤 反复发作。我们还将确定晚期复发者的肿瘤细胞是否更有可能 保留或获得了表达锡钙素的能力比那些早期 复发。如果我们发现锡钙素是晚期乳腺癌复发的特异性标志物，我们将寻求新的 在第二个乳腺癌队列和结直肠癌队列中验证结果的研究支持，以及 来研究破坏这一途径的药物。 晚期复发风险没有特定的标志。一种预测何时会发生复发的标记， 而不是是否会复发，将改变癌症的临床范式， 晚期复发风险。它将允许复发筛查策略的个性化，开发低- 当晚期复发风险上升时开始的毒性预防治疗，以及现有的个性化 关于从诊断开始的时间的辅助治疗。这个R21高风险、高回报的项目将启动一个 确定晚期复发风险的标志和降低或改善该风险的策略的计划。

PROJECT SUMMARY/ABSTRACT Advances in the effectiveness of breast cancer screening and treatment have reduced the breast cancer mortality rate over the last decades. These advances come from avoided recurrences, but also from delayed recurrences. The success of chemotherapy, endocrine therapy, and radiation therapy, is typically measured by a reduction in the risk of recurrence in the first five years after breast cancer diagnosis. Many recurrences, however, occur late; that is, more than five years after diagnosis. These recurrences erupt from single dormant cells or micro-metastases where tumor cell growth has been balanced by tumor cell death. How does a single cell, or a small colony of cells, survive for more than five years in a hostile microenvironment that, at least at the outset, often includes hypoxic climates induced by cancer therapies? One likely explanation is that tumors with the capability to recruit stanniocalcin are more likely to survive in this setting and to recur five or more years after diagnosis. Stanniocalcin is a hormone first discovered in bony fish, where it regulates the concentration of calcium at the gills. In humans, nerve cells, fat cells, heart cells, ova, and other long-lived cells recruit stanniocalcin as a survival strategy when they face hypoxic stress, helping them to live in sometimes harsh conditions by uncoupling proton transport from glycosylation in the mitochondria. Preliminary human evidence and in vitro studies show that tumor expression of stanniocalcin is a marker of recurrence risk, and particularly late recurrence risk. We propose, therefore, to use an existing biobank from ~1700 breast cancer patients (841 with recurrence and 841 matched controls) linked to complete clinical data and long-term follow-up for recurrence to investigate whether stanniocalcin expression is a specific marker for late recurrence risk. We will determine whether breast cancer patients with late recurrences were more likely to have had primary tumors that express stanniocalcin than breast cancer patients with early recurrences. We will also determine whether the tumor cells of those with late recurrence are more likely to have retained or acquired the ability to express stanniocalcin than the tumor cells of those with early recurrence. If we find that stanniocalcin is a specific marker for late breast cancer recurrence, we will seek new research support to validate the result in a second breast cancer cohort and in a colorectal cancer cohort, and to investigate drugs to disrupt the pathway. There is no specific marker for late recurrence risk. A marker that predicts when a recurrence will occur, rather than whether a recurrence will occur, would change the clinical paradigm for cancers with substantial late recurrence risk. It would allow personalization of recurrence screening strategies, development of low- toxicity prophylactic therapies that begin when the late recurrence risk rises, and personalization of existing adjuvant therapies with regard to time from diagnosis. This R21 high-risk, high-reward project will initiate a program to identify markers of late recurrence risk and strategies to reduce or ameliorate that risk.