A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-Derived Human Breast Cancer Xenograft Models
Jenny C. Chang, Qing Lai, Pavel Zuloaga, Amber M. Froehlich, Edward S. Chen, Jian Huang, Mario Giuliano, Sofie Claerhout, Gordon B. Mills, Chad A. Shaw, Suzanne A.W. Fuqua, Michael T. Lewis, Charles M. Perou, Mothaffar F. Rimawi, Alejandro Contreras, Carolina Gutiérrez, Anna Tsimelzon, Xiaomei Zhang, Sufeng Mao, Susan G. Hilsenbeck, M. F. Wu, Anne C. Pavlick, Helen Wong, Aleix Prat, Lisa Wiechmann, Ivana Petrović, Lacey E. Dobrolecki, Rachel Schiff, Melissa D. Landis
Abstract
Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis.