title: Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation.
abstract: 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 PI3K-targeted 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.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Christin
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20814, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maja H
authors.initials: MH
authors.lastname: Oktay
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: wenjun.guo@einstein.yu.edu.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Guo
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009940:Organoids; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D013234:Stem Cells; D004268:DNA-Binding Proteins
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins; C516766:Ptpn22 protein, mouse