Project 2: Therapeutic targeting of estrogen receptor beta in triple negative breast cancer

项目2：三阴性乳腺癌中雌激素受体β的治疗靶向

• 批准号: 10017908
• 负责人: John R. Hawse
• 金额: $ 28.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017908
• 关键词: Address; Agonist; Androgen Receptor; Biological Markers; Biopsy; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Proliferation; Characteristics; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cystatins; Data; Development; Diagnosis; Disease; Disease Management; ERBB2 gene; Endocrine; Epidermal Growth Factor Receptor; Estradiol; Estradiol Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Therapy; Event; Expression Profiling; Goals; In Vitro; Individual; Lead; Mediating; Messenger RNA; MicroRNAs; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nonmetastatic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Progesterone Receptors; Protein Family; Proteins; Residual Tumors; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; Transforming Growth Factor beta; Treatment Efficacy; Woman; Xenograft procedure; anti-cancer; base; cancer therapy; chemotherapy; cohort; genetic signature; improved; improved outcome; in vivo; malignant breast neoplasm; migration; mortality; new therapeutic target; patient population; patient response; receptor; response; side effect; targeted treatment; therapeutic biomarker; therapeutic target; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; Address; Agonist; Androgen Receptor; Biological Markers; Biopsy; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Proliferation; Characteristics; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cystatins; Data; Development; Diagnosis; Disease; Disease Management; ERBB2 gene; Endocrine; Epidermal Growth Factor Receptor; Estradiol; Estradiol Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Therapy; Event; Expression Profiling; Goals; In Vitro; Individual; Lead; Mediating; Messenger RNA; MicroRNAs; Modeling; Neoadjuvant Therapy; Neoplasm Metastasis; Nonmetastatic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Progesterone Receptors; Protein Family; Proteins; Residual Tumors; Resistance; Role; Series; Signal Transduction; Testing; Therapeutic; Transforming Growth Factor beta; Treatment Efficacy; Woman; Xenograft procedure; anti-cancer; base; cancer therapy; chemotherapy; cohort; genetic signature; improved; improved outcome; in vivo; malignant breast neoplasm; migration; mortality; new therapeutic target; patient population; patient response; receptor; response; side effect; targeted treatment; therapeutic biomarker; therapeutic target; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT: In 2015 it is estimated that more than 1.6 million women will develop breast cancer world-wide, of which nearly 20% will be diagnosed with a form of the disease referred to as triple negative breast cancer (TNBC) that lacks expression of estrogen receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2). For these reasons, targeted therapies are currently limited for this patient population. While chemotherapy improves the survival of TNBC patients, 5 year mortality rates approach 50% for individuals with residual disease after neoadjuvant treatment. It is therefore paramount to identify new drug targets and therapeutic strategies for women with TNBC. We and others have recently demonstrated that 30% of TNBCs express ERβ and have shown that ERβ expression is associated with improved survival in TNBC patients. Additionally, the large majority of ERβ+ TNBCs do not express the androgen receptor allowing for the potential expansion of endocrine related therapies into an additional subset of TNBC patients. To identify therapies that may have utility for the treatment of ERβ+ TNBC, we have developed ERβ expressing TNBC cell lines and have generated ERβ+ and ERβ- patient derived xenografts (PDX) from women with non-metastatic locally advanced TNBC. We show that activation of ERβ with estradiol significantly reduces cell proliferation and tumor growth, effects that appear to be mediated in part by a family of proteins known as the cystatins which are highly induced by ERβ in TNBC cells. Elevated cystatin levels lead to suppression of canonical TGFβ signaling, a pathway known to drive tumor progression, metastasis, and resistance to chemotherapy regimens. We have also shown that these same anti-cancer effects can be achieved with drugs such as LY500307 that specifically target ERβ allowing for the opportunity to develop cancer therapies that could avoid the negative side effects associated with estradiol. Based on these preliminary data, our central hypothesis is that therapeutic activation of ERβ will result in clinical benefit for patients with ERβ+ TNBC by regulating a series of events that involves the induction of cystatins and suppression of canonical TGFβ signaling. To test this hypothesis, the following Specific Aims are proposed: 1). Determine the role of cystatins, and their impact on TGFβ signaling, in mediating the anti-cancer effects of ERβ in TNBC and characterize the expression of these biomarkers in a large cohort of TNBC patients; 2). Characterize the in vivo effects of estradiol and LY500307 on ERβ+ TNBC PDXs; 3). Elucidate the therapeutic efficacy of estradiol in ERβ+ TNBC. To address these Specific Aims, we will employ multiple in vitro and in vivo approaches to fully characterize the mechanisms of action and anti-tumor activity of estradiol and ERβ specific agonists for the treatment of ERβ+ TNBC. Given the extremely poor outcomes in women with TNBC and the lack of targeted therapies for this group of patients, the proposed studies are of critical importance towards the goal of indentifying novel drug targets and therapeutic strategies to more effectively treat and manage this disease.

项目摘要/摘要： 据估计，2015年，超过160万妇女将在全球培养乳腺癌，其中几乎 20％将被诊断为一种疾病形式，称为三重阴性乳腺癌（TNBC） 雌激素受体α（ERα），孕酮受体（PR）和表皮生长因子受体的表达 2（Her2）。由于这些原因，目前，该患者人群的靶向疗法受到限制。尽管 化学疗法改善了TNBC患者的存活率，5年死亡率接近50％ 新辅助治疗后残留疾病。因此，确定新药物目标和 针对TNBC女性的治疗策略。我们和其他人最近证明了30％的TNBC 表达ERβ，并表明ERβ表达与TNBC患者的生存率提高有关。 此外，绝大多数ERβ+ TNBC不表达雄激素受体，从而允许潜力 内分泌相关疗法扩展到TNBC患者的另一个子集中。确定疗法 可能具有治疗ERβ+ TNBC的实用性，我们已经开发了ERβ表达TNBC细胞系，并且 已经产生了来自非转移性局部女性的ERβ+和ERβ-患者衍生的Xenographtics（PDX） 高级TNBC。我们表明，用雌二醇激活ERβ可以显着降低细胞的增殖和 肿瘤的生长，似乎是由一种被称为抑制蛋白的蛋白质介导的作用 TNBC细胞中的ERβ高度诱导。胱抑素水平升高导致抑制典型的TGFβ 信号传导，一种已知驱动肿瘤进展，转移和对化疗方案的耐药性的途径。 我们还表明，可以通过Ly500307等药物来实现这些相同的抗癌作用 特别靶向ERβ，允许有机会开发可能避免阴性的癌症疗法 与雌二醇相关的副作用。基于这些初步数据，我们的中心假设是 ERβ的治疗活化将通过调节A 一系列涉及伴有胱抑素和抑制规范TGFβ信号传导的事件。 为了检验这一假设，提出了以下特定目的：1）。确定胱抑素的作用及其 对TGFβ信号传导的影响，在介导ERβ在TNBC中的抗癌作用中并表征 这些生物标志物在大量TNBC患者中的表达； 2）。表征体内效应 ERβ+ TNBC PDX上的雌二醇和LY500307； 3）。阐明雌二醇在ERβ+中的治疗效率 TNBC。为了解决这些特定目标，我们将采用多种体外和体内方法来完全 表征雌二醇和ERβ特异性激动剂的作用机理和抗肿瘤活性 ERβ+ TNBC的处理。鉴于TNBC女性的结果极差，并且缺乏目标 对这组患者的疗法，拟议的研究至关重要 缩减新型药物靶标和治疗策略，以更有效地治疗和管理这种疾病。