NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34524841.
- Also identified by DOI 10.1126/sciadv.abc8145 and PMC identifier 8443188.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Most breast cancer deaths are caused by estrogen receptor-α–positive (ER<sup>+</sup>) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER<sup>+</sup> tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> breast cancers.