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Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

View ORCID ProfileLarissa Mourao, Amber L. Zeeman, Katrin E. Wiese, View ORCID ProfileAnika Bongaarts, View ORCID ProfileLieve L. Oudejans, Isabel Mora Martinez, View ORCID ProfileYorick B.C. van de Grift, View ORCID ProfileJos Jonkers, View ORCID ProfileRenée van Amerongen
doi: https://doi.org/10.1101/2021.06.22.449461
Larissa Mourao
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Amber L. Zeeman
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Katrin E. Wiese
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Anika Bongaarts
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Lieve L. Oudejans
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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  • ORCID record for Lieve L. Oudejans
Isabel Mora Martinez
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Yorick B.C. van de Grift
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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Jos Jonkers
##Oncode Institute and Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
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Renée van Amerongen
#Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Postbus 1212, 1000 BE, Amsterdam, the Netherlands
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  • For correspondence: r.vanamerongen@uva.nl
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ABSTRACT

In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE178321

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 22, 2021.
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Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium
Larissa Mourao, Amber L. Zeeman, Katrin E. Wiese, Anika Bongaarts, Lieve L. Oudejans, Isabel Mora Martinez, Yorick B.C. van de Grift, Jos Jonkers, Renée van Amerongen
bioRxiv 2021.06.22.449461; doi: https://doi.org/10.1101/2021.06.22.449461
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Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium
Larissa Mourao, Amber L. Zeeman, Katrin E. Wiese, Anika Bongaarts, Lieve L. Oudejans, Isabel Mora Martinez, Yorick B.C. van de Grift, Jos Jonkers, Renée van Amerongen
bioRxiv 2021.06.22.449461; doi: https://doi.org/10.1101/2021.06.22.449461

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