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.

项目摘要/摘要 乳腺癌筛查和治疗的有效性的进步已减少了乳房 癌症死亡率在过去几十年中。这些进步来自避免复发，但也来自 延迟复发。化学疗法，内分泌治疗和放射治疗的成功通常是 通过在乳腺癌诊断后的头五年中降低复发风险来衡量。许多 然而，复发发生迟到。也就是说，诊断后五年多。这些复发从 肿瘤细胞死亡已经平衡肿瘤细胞生长的单一休眠细胞或微焦点酶。如何 在敌对的微环境中，单个细胞或小菌落的生存超过五年 至少在一开始，通常包括癌症疗法引起的低氧气候？ 一种可能的解释是，具有招募Stanniocalcin能力的肿瘤更有可能生存 在这种情况下，诊断后五年或更长时间复发。 Stanniocalcin是最初发现的激素 骨鱼，调节ill钙的浓度。在人类中，神经细胞，脂肪细胞，心脏 细胞，OVA和其他长寿命的细胞在面临低氧应激时募集Stanniopalcin作为生存策略， 通过将质子转运从糖基化中解脱出来，帮助他们在恶劣的条件下生活 线粒体。初步的人类证据和体外研究表明，stanniocalcin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 约有1700名乳腺癌患者的生物库（841例复发和841个匹配的对照）与完成 临床数据和长期随访，以研究Stanniocalcin表达是否是特定的 后期复发风险的标记。我们将确定晚期复发的乳腺癌患者是否是 比早期的乳腺癌患者更有可能患有表达斯坦尼加仑素的原发性肿瘤 复发。我们还将确定患有晚期复发的肿瘤细胞是否更可能 比早期患者的肿瘤细胞保留或获得表达斯坦尼加仑素的能力 复发。如果我们发现stanniocalcin是晚期乳腺癌复发的特定标记，我们将寻求新的 研究支持以验证第二个乳腺癌队列和结直肠癌队列中的结果，以及 调查药物以破坏途径。 没有针对晚期复发风险的特定标记。预测何时复发的标记， 而不是是否会发生复发，而是会改变具有实质性的癌症的临床范式 晚期复发风险。它将允许个性化复发筛查策略，发展低 - 毒性预防性疗法开始时开始时，晚期复发风险升高，并对现有的个性化 关于诊断时间的辅助疗法。这个R21高风险，高回报项目将启动 计划确定后期复发风险的标记和降低或改善这种风险的策略。