Modeling breast cancer using CRISPR/Cas9-mediated engineering of human breast organoids

Johanna F Dekkers, James R Whittle, François Vaillant, Huei-Rong Chen, Caleb Dawson, Kevin Liu, Maarten Geurts, Marco J Herold, Hans Clevers, Geoffrey J Lindeman, Jane E Visvader

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Breast cancer is characterized by histological and functional heterogeneity, posing a clinical challenge for patient treatment. Emerging evidence suggests that the distinct subtypes reflect the repertoire of genetic alterations and the target cell. However, the precise initiating events that predispose normal epithelium to neoplasia are poorly understood. Here we demonstrate that breast epithelial organoids can be generated from human reduction mammoplasties (12 out of 12 donors), thus creating a tool to study the clonal evolution of breast cancer. To recapitulate de novo oncogenesis, we exploited CRISPR/Cas9 for targeted knock-out of four breast cancer-associated tumor suppressor genes (P53, PTEN, RB1, NF1) in mammary progenitor cells from six donors. Mutant organoids gained long-term culturing capacity and formed ER+ luminal tumors upon transplantation into mice for 1 out of 6 P53/PTEN/RB1-mutated and 3 out of 6 P53/PTEN/RB1/NF1-mutated lines. These organoids responded to endocrine therapy or chemotherapy, supporting the potential utility of this model to enhance our understanding of the molecular events that culminate in specific subtypes of breast cancer.

Original languageEnglish
JournalJournal of the National Cancer Institute
DOIs
Publication statusE-pub ahead of print - 07 Oct 2019

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