Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors

Stephanie L. Easter, Elizabeth H. Mitchell, Sarah E. Baxley, Renee Desmond, Andra R. Frost, Rosa Serra

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Abstract

Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/β-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/β-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was downregulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active β-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/β-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/β-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.

Original languageEnglish (US)
Article number0113247
JournalPLoS One
Volume9
Issue number11
DOIs
StatePublished - Nov 17 2014

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Easter, S. L., Mitchell, E. H., Baxley, S. E., Desmond, R., Frost, A. R., & Serra, R. (2014). Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors. PLoS One, 9(11), [0113247]. https://doi.org/10.1371/journal.pone.0113247