Singhal Hari, Greene Marianne E, Zarnke Allison L, Laine Muriel, Al Abosy Rose, Chang Ya-Fang, Dembo Anna G, Schoenfelt Kelly, Vadhi Raga, Qiu Xintao, Rao Prakash, Santhamma Bindu, Nair Hareesh B, Nickisch Klaus J, Long Henry W, Becker Lev, Brown Myles, Greene Geoffrey L
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.
Oncotarget. 2017 Sep 28;9(4):4282-4300. doi: 10.18632/oncotarget.21378. eCollection 2018 Jan 12.
Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.
在乳腺癌中开发有效的孕激素受体（PR）靶向疗法的主要障碍包括缺乏高度特异性的PR调节剂、对PR异构体和配体的促肿瘤或抗肿瘤网络了解不足，以及对PR与雌激素受体（ER）信号之间的相互作用理解不完整。通过对用各种临床相关的ER和PR靶向药物治疗的异种移植瘤进行基因组分析，我们描述了PR的激活或抑制如何差异地重新编程雌激素信号，导致转录组分离为单独的PR激动剂和拮抗剂介导的组。这些发现解决了关于PR激动剂和拮抗剂单独或与他莫昔芬联合用于乳腺癌治疗的临床效用的持续争议。此外，两种PR异构体PRA和PRB结合不同但重叠的基因组位点，并与不同的共调节因子相互作用，以差异地调节雌激素信号，从而产生促肿瘤或抗肿瘤作用。在这两种异构体中，PRA比PRB更显著地抑制基因表达和ER染色质结合。在富含PRA和PRB的患者肿瘤中观察到差异基因表达，并且富含PRA的基因特征具有较差的生存结果。为了支持富含PRA的肿瘤对抗孕激素的反应性，与PR拮抗剂而非PR激动剂相关的基因特征预测了更好的生存结果。与PR激动剂治疗相比，PR拮抗剂治疗带来的更好的患者生存率进一步体现在他莫昔芬与PR拮抗剂和调节剂联合治疗的更高的体内抗肿瘤活性上。这项研究表明，将由于另一种受体与其配体（激动剂或拮抗剂）的伴随相互作用而观察到的共同效应与独特的异构体和配体特异性效应区分开来，将为患者选择生物标志物的开发以及PR靶向疗法向临床的转化提供信息。
