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

斯钙素是否能预测晚期乳腺癌复发，还是纯属虚构？

• 批准号: 8692147
• 负责人: Timothy L. Lash
• 金额: $ 18.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692147
• 关键词: Adipocytes; Adjuvant Therapy; Affect; Antineoplastic Agents; Apoptosis; Attention; Biological Assay; Biological Markers; Biology; Breast Cancer Detection; Calcium; Cancer Patient; Cancer Prognosis; Cancer Survivor; Cardiac Myocytes; Case-Control Studies; Cell Death; Cell division; Cells; Characteristics; Climate; Clinical; Clinical Data; Colorectal Cancer; Development; Diagnosis; Disease; Distant; Effectiveness; Endocrine; Endocrine Glands; Environment; Equilibrium; Face; Fishes; Gills; Growth; Hormones; Human; Hypoxia; Immunologic Surveillance; In Vitro; Investments; Kidney; Lead; Life; Link; Malignant Neoplasms; Measures; Micrometastasis; Mind; Mitochondria; Molecular; Neoplasm Metastasis; Neurons; Normal Cell; Oocytes; Osteichthyes; Ovum; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Primary Neoplasm; Process; Protons; Provider; Radiation therapy; Recruitment Activity; Recurrence; Research Support; Risk; STC1 gene; STC2 gene; Signal Transduction; Solid Neoplasm; Staging; Stratification; Stress; Surface; Theca folliculi structure; Time; Tissues; Toxic effect; analog; assault; biobank; breast cancer diagnosis; calcium phosphate; cancer recurrence; cancer site; cancer therapy; cell growth; chemotherapy; cohort; follow-up; glycosylation; heart cell; high reward; high risk; hormone therapy; human STC1 protein; improved; inorganic phosphate; interstitial; malignant breast neoplasm; molecular marker; mortality; neoplastic cell; novel therapeutics; paracrine; prevent; prognostic; programs; prophylactic; public health relevance; screening; stanniocalcin 2; success; teleocalcin; trait; tumor

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.

项目总结/摘要 乳腺癌筛查和治疗有效性的进步减少了乳腺癌的发病率。 癌症死亡率在过去的几十年里。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， 通过乳腺癌诊断后前五年内复发风险的降低来衡量。许多 然而，复发发生较晚，即在诊断后五年以上。这些反复发作的疾病 单个休眠细胞或微转移，其中肿瘤细胞生长已被肿瘤细胞死亡平衡。如何 一个细胞或一个小的细胞群体在一个恶劣的微环境中存活超过五年 至少在一开始，经常包括癌症治疗引起的缺氧气候？ 一个可能的解释是，具有招募斯钙素能力的肿瘤更有可能存活 在这种情况下，并在诊断后五年或更长时间内复发。斯钙素是一种激素， 硬骨鱼，在那里它调节鳃的钙浓度。人类的神经细胞脂肪细胞心脏 细胞、卵母细胞和其它长寿细胞在它们面临缺氧应激时募集斯钙素作为存活策略， 通过将质子运输与糖基化解偶联，帮助它们在有时恶劣的条件下生活， 线粒体初步的人类证据和体外研究表明，肿瘤中斯钙素的表达是一个重要的因素。 复发风险的标志物，特别是晚期复发风险。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）的生物样本库， 临床数据和长期随访复发，以调查斯钙素表达是否是一种特异性的 晚期复发风险的标志物。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， 复发。我们还将确定那些晚期复发的肿瘤细胞是否更有可能 保留或获得了表达斯钙素的能力，而不是那些早期肿瘤细胞。 复发如果我们发现斯钙素是晚期乳腺癌复发的特异性标志物， 研究支持，以验证第二个乳腺癌队列和结直肠癌队列的结果，以及 来研究药物来破坏这一通路 没有晚期复发风险的特异性标志物。一种预测复发时间的标记， 而不是是否会复发，将改变癌症的临床模式， 晚期复发风险。它将允许复发筛查策略的个性化，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 辅助治疗与诊断时间有关。这个R21高风险，高回报的项目将启动一个 以识别晚期复发风险标记和降低或改善该风险的策略。