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: 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
• 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

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.

摘要 孕激素受体基因(Pgr)是雌激素受体激动剂(ER，α)的靶基因。因此，表达 乳腺腔癌孕酮受体(PR)是ER活性的标志物，预示着良好的反应 内分泌治疗。然而，ER+乳腺癌的复发发生在大约40%的淋巴结阳性患者中。 尽管阻止癌细胞增殖的乳腺癌治疗方法，如他莫昔芬，最初非常有效 有效的是，它们不能靶向缓慢增殖的细胞，包括癌症干细胞和祖细胞群体 (CSCs)会导致复发。对内分泌治疗的抵抗力也会随着时间的推移而发展。 临床研究支持PR在内分泌衰竭中的作用，但机制尚不清楚。事实上，公关 对内质网活动有深远的影响，尽管相对于内质网，对它们的研究还很少。两种PR亚型 在乳腺组织中与PGR基因表达相同的是：全长PR-B和截短PR-A。正常情况下 组织中，PR亚型最常见的功能是A：B异源二聚体。PR亚型表达不平衡是典型的 ER+乳腺癌，因此反映了A：A或B：B同源二聚体的存在，并与 不同的功能。这两种异构体也被乳房中普遍升高的信号通路严重改变 癌症。在MAPK或CDKs的作用下，Prs在Ser294(p-Prs)上被磷酸化，并产生ACT基因 与乳腺癌预后不良相关的方案。PR异构体失衡的ER+乳腺肿瘤表达 丰富的p-PR，提示有丝分裂信号转导激活和SR功能异常。 这一建议解决了p-PR通过ER依赖和 ER-独立函数。总而言之，这些由PR驱动的事件会产生内分泌抵抗，提高胰岛素水平 敏感性，并增加乳腺癌干细胞。我们认为p-PR通过2-2控制这些表型。 主要机制：1)通过调节适配蛋白、胰岛素受体底物来调节内质网功能 (IRS-1)，增加胰岛素敏感性，导致内分泌抵抗；以及2)诱发致癌的p- 由磷酸化的FOXO1分子介导的PR/FOXO1信号轴。在该支持信令的上下文中， PR可以从ER功能的抑制剂切换到在不同的目标基因上激活ER伙伴，这些靶基因驱动 晚期癌症表型。因此，PR是ER+乳腺癌进展的未被充分利用的驱动因素。 提出的目标是1)确定p-PR如何改变全球SR基因程序，并测试 胰岛素受体底物-1(IRS-1)作为关键配体非依赖的p-PR诱导基因；2)确定 P-PR/FOXO1轴驱动ER+乳腺癌；3)确定p-PR对ER+乳腺癌的贡献 使用患者来源的异种移植模型体内癌症进展。现在迫切需要划定 PR作为增殖和细胞命运转换/可塑性的驱动力，促进ER+肿瘤的进展。 发现公关的针对性行为将有助于为持久组合的发展铺平道路 阻断ER和PR的内分泌治疗，改善ER+乳腺癌患者的预后。