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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.

SUBMITTER: Watanabe K

PROVIDER: S-EPMC3913260 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Watanabe K K Fallahi M M Dai X X

Oncogene 20130121 5

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 Pygo ...[more]

PMID: 23334328

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Project description:BACKGROUND:Breast cancer is a heterogeneous disease. Hence, stratification of patients based on the subtype of breast cancer is key to its successful treatment. Among all the breast cancer subtypes, basal-like breast cancer is the most aggressive subtype with limited treatment options. Interestingly, we found focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase, is highly overexpressed and activated in basal-like breast cancer. METHODS:To understand the role of FAK in this subtype, we generated mice with conditional deletion of FAK and a knock-in mutation in its kinase domain in MMTV-Wnt1-driven basal-like mammary tumors. Tumor initiation, growth, and metastasis were characterized for these mice cohorts. Immunohistochemical and transcriptomic analysis of Wnt1-driven tumors were also performed to elucidate the mechanisms underlying FAK-dependent phenotypes. Pharmacological inhibition of FAK and mTOR in human basal-like breast cancer cell lines was also tested. RESULTS:We found that in the absence of FAK or its kinase function, growth and metastasis of the tumors were significantly suppressed. Furthermore, immunohistochemical analyses of cleaved caspase 3 revealed that loss of FAK results in increased tumor cell apoptosis. To further investigate the mechanism by which FAK regulates survival of the Wnt1-driven tumor cells, we prepared an isogenic pair of mammary tumor cells with and without FAK and found that FAK ablation increased their sensitivity to ER stress-induced cell death, as well as reduced tumor cell migration and tumor sphere formation. Comparative transcriptomic profiling of the pair of tumor cells and gene set enrichment analysis suggested mTOR pathway to be downregulated upon loss of FAK. Immunoblot analyses further confirmed that absence of FAK results in reduction of AKT and downstream mTOR pathways. We also found that inhibition of FAK and mTOR pathways both induces apoptosis, indicating the importance of these pathways in regulating cell survival. CONCLUSIONS:In summary, our studies show that in a basal-like tumor model, FAK is required for survival of the tumor cells and can serve as a potential therapeutic target.

Dataset Information

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

Publications

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

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