Promotion of ER+ Breast Cancer Progression in the Elderly

促进老年人乳腺癌进展

• 批准号: 10455463
• 负责人: Neil Carleton
• 金额: $ 4.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455463
• 关键词: Adverse effects; Age; Age-Years; Aging; Anti-Inflammatory Agents; Behavior; Biological; Biology; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Cancer Etiology; Cessation of life; Chronic; Clinical; Clinical Trials; Cytokine Receptors; DNA Methylation; Deimplementation; Development; Diagnosis; Disease; Disease-Free Survival; ESR1 gene; Elderly; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogen receptor positive; Estrogens; Estrone; Exhibits; Foundations; Future; Gene Expression; Genomics; Goals; Growth; Guidelines; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Investigation; Lead; Malignant Neoplasms; Mammary Neoplasms; Methylation; Modeling; Molecular; NF-kappa B; Organoids; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Physicians; Physiological; Plasma; Population; Proteins; Radiation therapy; Rattus; Receptor Signaling; Recurrence; Research Training; Risk; Risk Factors; Role; STAT3 gene; Sampling; Scientist; Sentinel Lymph Node Biopsy; Signal Transduction; Techniques; Testing; Therapeutic; Training; Translational Research; Woman; age related; aged; breast cancer progression; career; chemokine; cohort; cost; cytokine; epigenomics; hormone therapy; improved; inflammatory marker; inflammatory modulation; innovation; malignant breast neoplasm; middle age; neoplastic cell; new therapeutic target; older patient; overtreatment; patient population; spectrograph; standard care; transcriptome sequencing; transcriptomics; treatment guidelines; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY / ABSTRACT Breast cancer is the second leading cause of cancer-related deaths in women. Over two-thirds of all breast cancer cases are considered estrogen receptor positive (ER+). Significantly, ER+ breast cancer incidence correlates strongly with aging, rising to a peak incidence in women aged 70 years or older (elderly). Owing in large part to the differences in physiologic estrogen signaling and the chronic inflammatory state that develops as people age, ER+ breast cancer that develops in the elderly population exhibits distinct clinical and biologically behavior from ER+ breast cancer in younger cohorts. Clinically, while endocrine therapy continues to be a mainstay of treatment, there is a major push for de-implementation of invasive and adverse effect- causing interventions in the elderly that do not impact disease-specific survival. Our group has recently shown that in elderly patients with early stage ER+, clinically node-negative tumors, de-implementation of both sentinel lymph node biopsy and radiation therapy can be safely omitted without compromising local recurrence-free or disease-free survival. Biologically, intrinsic epigenomic and transcriptomic as well as changes to local breast microenvironment all contribute to a unique landscape for tumor pathogenesis in aged individuals. The interplay and disease-causing roles of these factors requires further investigation. We will investigate several key questions in this translational proposal: (1) What factors that arise in the backdrop of age-induced chronic inflammation may contribute to distinct tumor signaling in aged ER+ breast tumors? Using patient tumor and plasma samples, we will characterize cytokines, chemokines, and estrogen profiles, connecting these extrinsic factors with transcriptomic alterations in the tumor cell using RNA sequencing. (2) Can we mechanistically understand the crosstalk between altered inflammatory axis signaling and estrogen receptor signaling in ER+ breast cancer models? We hypothesize that the inflammatory cytokines and chemokines present in the breast microenvironment alter ER signaling through the estrogen- sensitive NF-kB / IL-6 / STAT3 inflammatory axis, and this may be a novel therapeutic target for treating elderly breast cancer. (3) Does pharmacological modulation of this pathway using low-cost, well-tolerated, readily available drugs result in stunted ER+ breast cancer growth? This proposal will ultimately lead to a better understanding of the unique molecular drivers of ER+ breast cancer in the elderly. Successful completion of these Aims will provide the foundation for future studies and clinical trials to better define treatment standards for elderly patients, who are traditionally both understudied and underrepresented in clinical trials. Further, this proposal will provide me with an exemplary translational platform and research training, working with a collaborative group of clinicians and scientists to launch my career as a physician scientist poised to both treat these patients and study their oncologic diseases.

项目摘要 /摘要 乳腺癌是女性与癌症相关死亡的第二大原因。超过三分之二的乳房 癌症病例被认为是雌激素受体阳性（ER+）。值得注意的是，ER+乳腺癌发病率 与衰老密切相关，在70岁或以上（老年人）的女性中升高到峰值发病率。下去 生理雌激素信号传导和发展的慢性炎症状态的差异很大 随着人们的年龄，在老年人群中发展的ER+乳腺癌表现出独特的临床和 来自年轻同龄人的ER+乳腺癌的生物学行为。临床上，内分泌疗法继续 作为治疗的主要手段，有一个主要的推动侵入性和不良反应 - 导致对老年人的干预措施不会影响疾病特异性生存。我们的小组最近显示了 在早期ER+的老年患者中 哨兵淋巴结活检和放射疗法可以安全省略而不损害本地 无复发或无病生存。在生物学上，内在的表观基因组和转录组以及 局部乳房微环境的变化都有助于衰老的肿瘤发病机理的独特景观 个人。这些因素的相互作用和引起疾病的作用需要进一步研究。 我们将在此翻译建议中调查几个关键问题：（1） 年龄引起的慢性炎症的背景可能导致年龄ER+乳房的明显肿瘤信号传导 肿瘤？使用患者肿瘤和血浆样品，我们将表征细胞因子，趋化因子和雌激素 轮廓，将这些外在因子与肿瘤细胞中的转录组改变联系起来 测序。 （2）我们可以机械地理解改变炎症轴信号传导之间的串扰 ER+乳腺癌模型中的雌激素受体信号传导？我们假设炎症 乳腺微环境中存在的细胞因子和趋化因子通过雌激素改变ER信号传导 敏感的NF-KB / IL-6 / STAT3炎症轴，这可能是治疗老年人的新型治疗靶点 乳腺癌。 （3）使用低成本，耐受性良好，易于调制该途径的药理调制 可用的药物会导致ER+乳腺癌生长发育迟缓？ 该建议最终将使人们更好地了解ER+的独特分子驱动因素 老年人的乳腺癌。这些目标的成功完成将为以后的研究奠定基础 和临床试验以更好地定义老年患者的治疗标准，他们传统上都是 在临床试验中研究和人为不足。此外，该建议将为我提供一个模范 转化平台和研究培训，与临床医生和科学家的合作小组合作 启动我作为一名医生科学家的职业，准备对待这些患者并研究其肿瘤学 疾病。