Most breast cancer deaths are caused by estrogen receptor-α–positive (ER⁺) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER⁺ tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER⁺ breast cancer. Because mouse prolactin fails to activate hPRL receptors, we developed a prolactin-humanized Nod-SCID-IL2Rγ (NSG) mouse (NSG-Pro) with physiological hPRL levels. Here, we show that NSG-Pro mice facilitate establishment of therapy-naïve, estrogen-dependent PDX tumors that progress to lethal metastatic disease. Preclinical trials provide first-in-mouse efficacy of pharmacological hPRL suppression on residual ER⁺ human breast cancer metastases and document divergent biology and drug responsiveness of tumors grown in NSG-Pro versus NSG mice. Oncogenomic analyses of PDX lines in NSG-Pro mice revealed clinically relevant therapy-resistance mechanisms and unexpected, potently actionable vulnerabilities such as DNA-repair aberrations. The NSG-Pro mouse unlocks previously inaccessible precision medicine approaches for ER⁺ breast cancers.

中文翻译：

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NSG-Pro 小鼠模型，用于揭示人类管腔乳腺癌的耐药机制和独特的脆弱性

大多数乳腺癌死亡是由雌激素受体-α阳性 (ER ⁺ ) 疾病引起的。缺乏概括转移进展和临床相关治疗耐药性的初治 ER ^{+肿瘤模型阻碍了临床前进展。人催乳素 (hPRL) 是原发性和转移性 ER +}乳腺癌的危险因素。由于小鼠催乳素无法激活 hPRL 受体，我们开发了具有生理 hPRL 水平的催乳素人源化 Nod-SCID-IL2Rγ (NSG) 小鼠 (NSG-Pro)。在这里，我们表明 NSG-Pro 小鼠有助于建立未接受过治疗的雌激素依赖性 PDX 肿瘤，这些肿瘤会发展为致命的转移性疾病。^{临床前试验提供了药物 hPRL 抑制对残留 ER +}的首次小鼠疗效人类乳腺癌转移并记录在 NSG-Pro 和 NSG 小鼠中生长的肿瘤的不同生物学和药物反应性。NSG-Pro 小鼠 PDX 系的致癌基因组学分析揭示了临床相关的治疗耐药机制和意想不到的、有效的可操作漏洞，例如 DNA 修复畸变。NSG-Pro 鼠标为 ER ⁺乳腺癌解锁了以前无法获得的精准医学方法。