title: Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice.
abstract: Little is known about chromatin mechanisms that regulate tumor-initiating cells that are proposed to be responsible for tumor recurrence and relapse. We have previously shown that Pygopus 2 (Pygo2), a chromatin effector and context-dependent Wnt signaling coactivator, regulates mammary gland development by expanding epithelial stem/progenitor cells. However, the role of Pygo2 in mammary tumorigenesis in vivo remains to be addressed. In this study, we show that epithelia-specific ablation of Pygo2 in MMTV-Wnt1 transgenic mice results in delayed mammary ductal elongation, but the hyperbranching phenotype, aberrant accumulation of stem/progenitor-like cells, and canonical Wnt signaling output are largely unaffected. Chronic loss of Pygo2 significantly delays mammary tumor onset in MMTV-Wnt1 females, whereas acute deletion of Pygo2 in MMTV-Wnt1 tumor cells leads to a significant decrease in their tumor-initiating capability upon transplantation. Finally, we provide evidence supporting a role for Pygo2 in modulating the lineage potential of MMTV-Wnt1 tumor initiating cells. Collectively, our results suggest that Pygo2 acts at a step downstream of mammary stem cell accumulation to facilitate transformation, and that it regulates the tumor initiating capacity and lineage preference of the already transformed mammary cells, in MMTV-Wnt1 mice. These findings offer valuable insights into our understanding of the molecular basis of heterogeneity within breast tumors.
authors: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors: K
authors: K
authors: Watanabe
authors: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors: M
authors: M
authors: Fallahi
authors: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors: X
authors: X
authors: Dai
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002843:Chromatin / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism* / Q000821:virology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology; D011774:Pyrvinium Compounds / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000871:Anthelmintics; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D011774:Pyrvinium Compounds; D034741:RNA, Small Interfering; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C495570:pygopus 2 protein, mouse; C024631:pyrvinium