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

描述(申请人提供)：在过去的几十年里，乳腺癌筛查和治疗的有效性的进步降低了乳腺癌的死亡率。这些进步来自避免复发，但也来自延迟复发。化疗、内分泌治疗和放射治疗的成功，通常是通过乳腺癌确诊后头五年复发风险的降低来衡量的。然而，许多复发发生在很晚的时候；即在确诊后五年以上。这些复发源于单个休眠细胞或微转移，在这些细胞中，肿瘤细胞的生长已经被肿瘤细胞死亡所平衡。单个细胞或一小群细胞如何在恶劣的微环境中存活五年以上，至少在一开始，这种微环境通常包括癌症治疗导致的低氧环境？一种可能的解释是，具有招募锡钙素能力的肿瘤更有可能在这种情况下存活，并复发5或 在确诊后又过了几年。斯丹尼卡素是一种最先在硬骨鱼中发现的荷尔蒙，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、卵细胞和其他长寿细胞在面临低氧应激时会招募锡钙素作为一种生存策略，通过将线粒体中的质子运输与糖基化解偶联来帮助它们在有时恶劣的条件下生活。初步的人类证据和体外研究表明，肿瘤中锡钙素的表达是复发风险的标志，尤其是晚期复发风险。因此，我们建议使用来自约1700名乳腺癌患者(841名复发患者和841名匹配对照)的现有生物库，与完整的临床数据和复发的长期随访相关联，以研究锡钙素的表达是否为晚期复发风险的特异性标志。我们将确定晚期复发的乳腺癌患者是否比早期复发的乳腺癌患者更有可能患有表达锡钙素的原发肿瘤。我们还将确定晚期复发者的肿瘤细胞是否比早期复发者的肿瘤细胞更有可能保留或获得表达锡钙素的能力。如果我们发现锡钙素是晚期乳腺癌复发的特异性标志物，我们将寻求新的研究支持，以验证在第二个乳腺癌队列和结直肠癌队列中的结果，并研究干扰该途径的药物。晚期复发风险没有特定的标志。预测复发时间的标志物，而不是是否会复发的标志物，将改变具有相当大的晚期复发风险的癌症的临床范例。它将允许复发筛查策略的个性化，当晚期复发风险上升时开始的低毒预防疗法的开发，以及关于从 诊断。这个R21高风险、高回报的项目将启动一项计划，以确定晚期复发风险的标志和降低或改善该风险的策略。

DESCRIPTION (provided by applicant): 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.