Journal
CELL REPORTS
Volume 16, Issue 12, Pages 3146-3156Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.08.048
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Funding
- Einstein Cancer Center Support Grant [P30 CA013330]
- New York State Department of Health (NYSTEM Program) [C029154]
- NYSTEM [C028109, C029571]
- Susan Komen for the Cure [CCR12224440]
- V Foundation for Cancer Research
- Training Program in Cellular and Molecular Biology and Genetics [2T32GM007491-36]
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Cancer genomics has provided an unprecedented opportunity for understanding genetic causes of human cancer. However, distinguishing which mutations are functionally relevant to cancer pathogenesis remains a major challenge. We describe here a mammary stem cell (MaSC) organoid-based approach for rapid generation of somatic genetically engineered mouse models (GEMMs). By using RNAi and CRISPR-mediated genome engineering in MaSC-GEMMs, we have discovered that inactivation of Ptpn22 or Mll3, two genes mutated in human breast cancer, greatly accelerated PI3K-driven mammary tumorigenesis. Using these tumor models, we have also identified genetic alterations promoting tumor metastasis and causing resistance to PI3Ktargeted therapy. Both Ptpn22 and Mll3 inactivation resulted in disruption of mammary gland differentiation and an increase in stem cell activity. Mechanistically, Mll3 deletion enhanced stem cell activity through activation of the HIF pathway. Thus, our study has established a robust in vivo platform for functional cancer genomics and has discovered functional breast cancer mutations.
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