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

• 批准号: 9884201
• 负责人: Carol A Lange
• 金额: $ 61.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/9884201
• 关键词: Adaptor Signaling Protein; Address; Adrenergic alpha-Antagonists; Advanced Malignant Neoplasm; Antiestrogen Therapy; Binding; Binding Proteins; Biological Markers; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Cell Proliferation; Cells; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; 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; Lead; Length; Ligands; MAP Kinase Gene; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; 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; Regulation; Research Support; Resistance; Role; Side; Signal Pathway; Signal Transduction; Social Network; Tamoxifen; Testing; Time; Woman; Work; Xenograft Model; Xenograft procedure; advanced disease; base; 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/antagonist; insulin sensitivity; malignant breast neoplasm; mortality; new therapeutic target; novel; overexpression; prevent; progenitor; progesterone receptor A; progesterone receptor B; programs; response; sensor; stem; stem cells; targeted treatment; therapeutic target; therapy development; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression

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 孕酮受体基因（PGR）是雌激素受体-α（ER）靶基因。那，表达 腔乳腺癌中的孕酮受体（PR）是活性ER的标志，可以预测良好的反应 进行内分泌疗法。然而，在约40％的淋巴结阳性患者中，ER+乳腺癌的复发发生。 尽管阻止癌细胞增殖的乳腺癌治疗（例如他莫昔芬）最初非常非常 有效，它们无法靶向缓慢增殖的细胞，包括癌症和祖细胞群体 （CSC）有助于复发。随着时间的流逝，对基于内分泌的疗法的耐药性也会发展出来。 临床研究支持PR在内分泌衰竭中的作用，但这些机制尚不清楚。实际上，PR 尽管与ER相对于ER广为人知，但对ER活动有深远的影响。两个PR同工型 从乳腺组织中的PGR基因同样表达：全长PR-B和截短的PR-A。正常 组织，PR同工型最常用作A：B杂二聚体。 PR同工型的不平衡表达典型 ER+乳腺癌，因此反映了A：A或B：B：B的存在，具有重叠和 不同的功能。两种同工型也通过乳房中通常升高的信号通路进行了重大修饰 癌症。为了响应MAPK或CDK，将PRS磷酸化在Ser294（P-PRS）上，并制定基因 与乳腺癌不良结局相关的程序。 ER+乳腺肿瘤与PR同工型不平衡快递 丰富的P-PRS，指示激活的有丝分裂信号转导和异常SR功能。 该提议解决了以下假设，即P-PR通过ER依赖性和 无权依赖性功能。这些PR驱动的事件会议会议内分泌抗性，增强了胰岛素 敏感性并增加乳腺癌干细胞。我们建议p-prs通过2控制这些表型 主要机制：1）调节衔接蛋白，胰岛素受体底物调节ER功能 （IRS-1），提高胰岛素敏感性，导致内分泌耐药性； 2）唤起致癌p- 由磷酸化FOXO1分子介导的PR/FOXO1信号轴。在这个亲信号的环境中 PR可以从ER功能的抑制剂切换到激活ER伴侣在不同的靶基因的驱动基因 晚期癌症表型。因此，PR是ER+乳腺癌进展的开发率不足。 拟议的目的是1）确定P-PRS如何改变全球SR基因程序并测试 胰岛素受体底物 - 一个（IRS-1）作为关键配体独立于P-PR诱导的基因； 2）确定如何 P-PR/FOXO1轴驱动ER+乳腺癌； 3）确定p-prs对ER+乳房的贡献 使用患者衍生的异种移植模型在体内癌症进展。迫切需要描述 PR作为促进ER+肿瘤进展的增殖和细胞脂肪转变/可塑性的驱动因素的作用。 发现PRS的有针对性动作将有助于开发耐用组合的道路 阻断ER和PR的内分泌疗法，改善了ER+乳腺癌患者的结局。