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Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice

Oncogene volume 33, pages 632–642 (2014)Cite this article

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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.

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Abbreviations

FACS:

Fluorescence-activated cell sorting

GSEA:

Gene set enrichment analysis

MaSC:

Mammary stem cell

MG:

Mammary gland

MMTV:

Mouse mammary tumor virus

Pygo2:

Pygopus 2

SSKO:

Skin/mammary epithelia-specific knockout.

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Acknowledgements

We thank the UCI Genomics High Throughput Facility and Sue and Bill Gross Stem Cell Research Center Core Facility (Vanessa Scarfone) for expert service, Yi Li and Julie Serge for the generous gifts of MMTV-Wnt1 mice and keratin antibodies, respectively, and Eva Lee for discussions. This work was supported by Susan G Komen grant KG110897 and NIH Grant R01-GM083089 (to XD). KW was supported by a U.S. Department of Defense Breast Cancer Research Program. (DOD BCRP) Postdoctoral Fellowship (W81XWH-10-1-0383).

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  1. Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA

    K Watanabe, M Fallahi & X Dai

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  1. K Watanabe
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Correspondence to X Dai.

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Watanabe, K., Fallahi, M. & Dai, X. Chromatin effector Pygo2 regulates mammary tumor initiation and heterogeneity in MMTV-Wnt1 mice. Oncogene 33, 632–642 (2014). https://doi.org/10.1038/onc.2012.620

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