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.
Recommended CitationSun, Yunguang; Yang, Ning; Utama, Fransiscus E; Udhane, Sameer S; Zhang, Junling; Peck, Amy R; Yanac, Alicia; Duffey, Katherine; Langenheim, John F; Udhane, Vindhya; Xia, Guanjun; Peterson, Jess F; Jorns, Julie M; Nevalainen, Marja T; Rouet, Romain; Schofield, Peter; Christ, Daniel; Ormandy, Christopher J; Rosenberg, Anne; I Chervoneva; Tsaih, Shirng-Wern; Flister, Michael J; Fuchs, Serge Y; Wagner, Kay-Uwe; and Rui, Hallgeir, "NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers" (2021). Department of Surgery Faculty Papers. Paper 203.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.