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Progesterone Receptor (PR) Signaling Cross Talk Drives ER+ Breast Cancer

黄体酮受体 (PR) 信号串扰导致 ER 乳腺癌

基本信息

批准号：
10593962
负责人：
Carol A Lange
金额：
$ 58.99万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-13 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593962
关键词：
Ablation Adaptor Signaling Protein Address Adrenergic alpha-Antagonists Advanced Malignant Neoplasm Anti-Progestin Antiestrogen Therapy Binding Binding Proteins Biological Markers Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cell Proliferation Cells ChIP-seq Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Cytoplasm Darkness Development Disease Disease Progression Distant Metastasis Drug Combinations Economic Burden Endocrine Estrogen Antagonists Estrogen Receptor alpha Estrogen receptor positive Event FOXO1A gene Failure Gene Expression Genes Genetic Transcription Gonadal Steroid Hormones Growth Growth Factor Growth Factor Receptors Hormones Human In Vitro Insulin Receptor Knock-in Length Ligands MAP Kinase Gene Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mass Spectrum Analysis Mediating Messenger RNA Metastatic/Recurrent Modeling Mus Neoplasm Metastasis Normal tissue morphology Oncogenic Organoids Outcome Patient-Focused Outcomes Patients Phenotype Phosphorylation Population Population Biology Positive Lymph Node Postmenopause Primary Neoplasm Progesterone Receptors Proliferating Protein Isoforms Proteins Receptor Gene Receptor Signaling Recurrence Recurrent Malignant Neoplasm Regulation Research Support Resistance Role Side Signal Pathway Signal Transduction Social Network Tamoxifen Testing Time Woman Work advanced disease breast cancer progression cancer biomarkers cancer cell cancer recurrence cancer stem cell disorder control experience gene product high risk hormone sensitivity hormone therapy improved improved outcome in vivo inhibitor insulin sensitivity malignant breast neoplasm mortality new therapeutic target novel overexpression patient derived xenograft model prevent progenitor progesterone receptor A progesterone receptor B programs response sensor stem stem cells targeted treatment therapeutic target transcriptome sequencing treatment response tumor tumor growth tumor microenvironment tumor progression

项目摘要

Abstract The progesterone receptor gene (PGR) is an estrogen receptor-α (ER) target gene. Thus, expression of progesterone receptors (PRs) in luminal breast cancers is a marker of active ER and predicts good response to endocrine therapy. However, recurrence of ER+ breast cancer occurs in ~40% of node-positive patients. Although breast cancer treatments that halt cancer cell proliferation, such as tamoxifen, are initially very effective, they fail to target slowly proliferating cells, including cancer stem and progenitor cell populations (CSCs) that contribute to recurrence. Resistance to endocrine-based therapies also develops over time. Clinical research supports a role for PR in endocrine failure, but the mechanisms are unknown. In fact, PRs have a profound impact on ER activity, although they are grossly understudied relative to ER. Two PR isoforms are equally expressed from the PGR gene in breast tissues: full-length PR-B and truncated PR-A. In normal tissues, PR isoforms most often function as A:B heterodimers. Imbalanced expression of PR isoforms typifies ER+ breast cancer, and thus reflects the presence of either A:A or B:B homodimers with overlapping and distinct functions. Both isoforms are also heavily modified by signaling pathways commonly elevated in breast cancer. In response to MAPKs or CDKs, PRs are phosphorylated on Ser294 (p-PRs) and enact gene programs associated with poor breast cancer outcome. ER+ breast tumors with PR isoform imbalance express abundant p-PRs, indicative of activated mitogenic signal transduction and aberrant SR function. This proposal addresses the hypothesis that p-PR modulates disease progression through ER-dependent and ER-independent functions. Together, these PR-driven events confer endocrine resistance, heighten insulin sensitivity, and increase breast cancer stem cells. We propose that p-PRs control these phenotypes through 2 primary mechanisms: 1) modulating ER function by regulating the adapter protein, insulin receptor substrate (IRS-1), increasing insulin sensitivity, resulting in endocrine resistance; and 2) evoking an oncogenic p- PR/FOXO1 signaling axis that is mediated by phosphorylated FOXO1 molecules. In this pro-signaling context, PRs can switch from inhibitors of ER function to activating ER partners at distinct target genes that drive advanced cancer phenotypes. PRs are thus under-exploited drivers of ER+ breast cancer progression. The proposed aims are 1) to determine how p-PRs alter global SR gene programs and to test the role of the insulin-receptor substrate-one (IRS-1) as a key ligand-independent p-PR-induced gene; 2) to determine how the p-PR/FOXO1 axis drives ER+ breast cancer; and 3) to determine the contribution of p-PRs to ER+ breast cancer progression in vivo using patient-derived xenograft models. There is an urgent need to delineate the actions of PRs as drivers of proliferation and cell fate transitions/plasticity that promote ER+ tumor progression. The discovery of targetable actions of PRs will help pave the way for development of durable combination endocrine therapies that block both ER and PRs, improving outcomes for patients with ER+ breast cancer.

抽象的孕激素受体基因（PGR）是雌激素受体-α（ER）靶基因。因此，表达腔内乳腺癌中的孕酮受体 (PR) 是活性 ER 的标志物，可预测良好的反应到内分泌治疗。然而，约 40% 的淋巴结阳性患者会出现 ER+ 乳腺癌复发。尽管阻止癌细胞增殖的乳腺癌治疗方法（例如他莫昔芬）最初非常有效虽然有效，但它们无法靶向缓慢增殖的细胞，包括癌症干细胞和祖细胞群（CSC）有助于复发。随着时间的推移，对内分泌治疗的耐药性也会出现。临床研究支持 PR 在内分泌衰竭中发挥作用，但其机制尚不清楚。事实上，PR 尽管相对于 ER 而言，它们的研究还很不足，但它们对 ER 活动具有深远的影响。两种 PR 亚型乳腺组织中 PGR 基因的表达相同：全长 PR-B 和截短的 PR-A。正常情况下在组织中，PR 同工型通常以 A:B 异二聚体的形式发挥作用。 PR 异构体表达不平衡的典型表现 ER+ 乳腺癌，因此反映了存在重叠和重叠的 A:A 或 B:B 同二聚体不同的功能。两种同工型也被乳腺中普遍升高的信号通路严重修饰癌症。响应 MAPK 或 CDK，PR 在 Ser294 (p-PR) 上磷酸化并激活基因与乳腺癌不良结果相关的计划。 PR 亚型不平衡的 ER+ 乳腺肿瘤表达丰富的 p-PR，表明激活的有丝分裂信号转导和异常的 SR 功能。该提案提出了这样的假设：p-PR 通过 ER 依赖性和调节疾病进展独立于 ER 的功能。这些 PR 驱动的事件共同导致内分泌抵抗，提高胰岛素水平敏感性，并增加乳腺癌干细胞。我们建议 p-PR 通过 2 控制这些表型主要机制：1）通过调节接头蛋白、胰岛素受体底物来调节 ER 功能 (IRS-1)，增加胰岛素敏感性，导致内分泌抵抗； 2) 诱发致癌 p- PR/FOXO1 信号轴由磷酸化 FOXO1 分子介导。在这种支持信号传递的背景下， PR 可以从 ER 功能抑制剂转变为激活驱动不同靶基因的 ER 伴侣晚期癌症表型。因此，PR 是 ER+ 乳腺癌进展的未充分利用的驱动因素。拟议的目标是 1) 确定 p-PR 如何改变全局 SR 基因程序并测试 p-PR 的作用胰岛素受体底物一 (IRS-1) 作为关键的配体独立 p-PR 诱导基因； 2）确定如何 p-PR/FOXO1 轴驱动 ER+ 乳腺癌； 3) 确定 p-PR 对 ER+ 乳房的贡献使用患者来源的异种移植模型进行体内癌症进展。迫切需要划定 PR 作为增殖和细胞命运转变/可塑性驱动因素的作用，促进 ER+ 肿瘤进展。 PR的靶向作用的发现将有助于为持久组合的开发铺平道路同时阻断 ER 和 PR 的内分泌疗法，可改善 ER+ 乳腺癌患者的预后。