Mammary-Stem-Cell-Based Somatic Mouse Models Reveal Breast Cancer Drivers Causing Cell Fate Dysregulation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2016 Sep 23

PMID 27653681

Citations 34

Authors

Zheng Zhang

John R Christin

Chunhui Wang

Kai Ge

Maja H Oktay

Wenjun Guo

Affiliations

Soon will be listed here.

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.

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References

Meyer D, Brinkhaus H, Muller U, Muller M, Cardiff R, Bentires-Alj M . Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res. 2011; 71(13):4344-51. DOI: 10.1158/0008-5472.CAN-10-3827. View

Adams J, Xu K, Liu J, Agamez N, Loch A, Wong R . Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res. 2011; 71(7):2706-17. DOI: 10.1158/0008-5472.CAN-10-0738. View

Elenbaas B, Spirio L, Koerner F, Fleming M, Zimonjic D, Donaher J . Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 2001; 15(1):50-65. PMC: 312602. DOI: 10.1101/gad.828901. View

Park K, Kwak K, Kim J, Lim S, Han S . c-myc amplification is associated with HER2 amplification and closely linked with cell proliferation in tissue microarray of nonselected breast cancers. Hum Pathol. 2005; 36(6):634-9. DOI: 10.1016/j.humpath.2005.04.016. View

Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A . Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med. 2011; 17(9):1116-20. PMC: 3169724. DOI: 10.1038/nm.2402. View

Koren S, Reavie L, Couto J, De Silva D, Stadler M, Roloff T . PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours. Nature. 2015; 525(7567):114-8. DOI: 10.1038/nature14669. View

Welm B, Dijkgraaf G, Bledau A, Welm A, Werb Z . Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer. Cell Stem Cell. 2008; 2(1):90-102. PMC: 2276651. DOI: 10.1016/j.stem.2007.10.002. View

Arial Zeng Y, Nusse R . Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell. 2010; 6(6):568-77. PMC: 2917779. DOI: 10.1016/j.stem.2010.03.020. View

Folkes A, Ahmadi K, Alderton W, Alix S, Baker S, Box G . The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . J Med Chem. 2008; 51(18):5522-32. DOI: 10.1021/jm800295d. View

10.

Srinivasan L, Sasaki Y, Calado D, Zhang B, Paik J, DePinho R . PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009; 139(3):573-86. PMC: 2787092. DOI: 10.1016/j.cell.2009.08.041. View

11.

Cho Y, Hong T, Hong S, Guo H, Yu H, Kim D . PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007; 282(28):20395-406. PMC: 2729684. DOI: 10.1074/jbc.M701574200. View

12.

Van Keymeulen A, Rocha A, Ousset M, Beck B, Bouvencourt G, Rock J . Distinct stem cells contribute to mammary gland development and maintenance. Nature. 2011; 479(7372):189-93. DOI: 10.1038/nature10573. View

13.

Moody S, Sarkisian C, Hahn K, Gunther E, Pickup S, Dugan K . Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell. 2002; 2(6):451-61. DOI: 10.1016/s1535-6108(02)00212-x. View

14.

Muller W, Sinn E, Pattengale P, Wallace R, Leder P . Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 1988; 54(1):105-15. DOI: 10.1016/0092-8674(88)90184-5. View

15.

Shilatifard A . The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem. 2012; 81:65-95. PMC: 4010150. DOI: 10.1146/annurev-biochem-051710-134100. View

16.

Wang D, Cai C, Dong X, Yu Q, Zhang X, Yang L . Identification of multipotent mammary stem cells by protein C receptor expression. Nature. 2014; 517(7532):81-4. DOI: 10.1038/nature13851. View

17.

Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat M, Oakes S . Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell. 2008; 3(4):429-41. DOI: 10.1016/j.stem.2008.08.001. View

18.

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View

19.

Van Dyke T, Jacks T . Cancer modeling in the modern era: progress and challenges. Cell. 2002; 108(2):135-44. DOI: 10.1016/s0092-8674(02)00621-9. View

20.

Van Keymeulen A, Lee M, Ousset M, Brohee S, Rorive S, Giraddi R . Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature. 2015; 525(7567):119-23. DOI: 10.1038/nature14665. View