NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers. Sci Adv 2021 Sep 17;7(38):eabc8145
Date
09/16/2021Pubmed ID
34524841Pubmed Central ID
PMC8443188DOI
10.1126/sciadv.abc8145Scopus ID
2-s2.0-85115168052 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Sun Y, Yang N, Utama FE, Udhane SS, Zhang J, Peck AR, Yanac A, Duffey K, Langenheim JF, Udhane V, Xia G, Peterson JF, Jorns JM, Nevalainen MT, Rouet R, Schofield P, Christ D, Ormandy CJ, Rosenberg AL, Chervoneva I, Tsaih SW, Flister MJ, Fuchs SY, Wagner KU, Rui HAuthors
Julie M. Jorns MD Professor in the Pathology department at Medical College of WisconsinYunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin
