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.
Sun, 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.
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