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

摘要 孕激素受体基因（PGR）是雌激素受体α（ER）的靶基因。因此，表达 在管腔型乳腺癌中，孕酮受体（PR）是ER活性的标志物，可预测良好的反应 内分泌治疗然而，ER+乳腺癌复发发生在~40%的淋巴结阳性患者中。 虽然阻止癌细胞增殖的乳腺癌治疗方法，如他莫昔芬，最初是非常有效的。 有效的，他们不能靶向缓慢增殖的细胞，包括癌症干细胞和祖细胞群 （CSCs），这有助于复发。随着时间的推移，对内分泌疗法的耐药性也会逐渐形成。 临床研究支持PR在内分泌衰竭中的作用，但其机制尚不清楚。事实上，PR 对ER活动产生深远影响，尽管相对于ER，它们的研究还非常不足。两种PR亚型 从乳腺组织中的PGR基因同等表达：全长PR-B和截短的PR-A。正常 在组织中，PR同种型最常作为A：B异二聚体起作用。PR亚型的不平衡表达 ER+乳腺癌，因此反映了A：A或B：B同源二聚体的存在， 不同的功能。这两种亚型也被乳腺癌中通常升高的信号通路严重修饰。 癌作为对MAPK或CDK的应答，PR在Ser 294（p-PR）上被磷酸化，并启动基因 与乳腺癌预后不良相关的项目。PR亚型失衡的ER+乳腺肿瘤表达 丰富的p-PR，表明激活的促有丝分裂信号转导和异常的SR功能。 这一提议提出了一个假设，即p-PR通过ER依赖性调节疾病进展， ER独立功能。总之，这些PR驱动的事件赋予内分泌抵抗， 增加乳腺癌干细胞。我们认为p-PRs通过2 主要机制：1）通过调节衔接蛋白、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;和2）引起致癌p- PR/FOXO 1信号轴由磷酸化FOXO 1分子介导。在这种亲信号的情况下， PR可以从ER功能的抑制剂转变为在不同的靶基因上激活ER伴侣， 晚期癌症表型因此，PR是ER+乳腺癌进展的驱动因素。 提出的目标是：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1（IRS-1）作为一个关键的配体非依赖性p-PR诱导基因; 2）确定如何 p-PR/FOXO 1轴驱动ER+乳腺癌;和3）确定p-PR对ER+乳腺癌的贡献 使用患者来源的异种移植物模型在体内研究癌症进展。迫切需要划定 PR作为促进ER+肿瘤进展的增殖和细胞命运转变/可塑性的驱动因素的作用。 发现PR的靶向作用将有助于为持久组合的发展铺平道路 阻断ER和PR的内分泌疗法，改善ER+乳腺癌患者的预后。

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.