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Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer

Author

Listed:
  • Pauliina M. Munne

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Lahja Martikainen

    (Aalto University School of Science)

  • Iiris Räty

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Kia Bertula

    (Aalto University School of Science)

  • Nonappa

    (Aalto University School of Science
    Aalto University School of Chemical Engineering)

  • Janika Ruuska

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Hanna Ala-Hongisto

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Aino Peura

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Babette Hollmann

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Lilya Euro

    (Biomedicum Helsinki, University of Helsinki)

  • Kerim Yavuz

    (University of Helsinki)

  • Linda Patrikainen

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Maria Salmela

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Juho Pokki

    (Aalto University)

  • Mikko Kivento

    (University of Helsinki)

  • Juho Väänänen

    (University of Helsinki)

  • Tomi Suomi

    (University of Turku and Åbo Akademi University)

  • Liina Nevalaita

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Minna Mutka

    (Helsinki University Central Hospital and University of Helsinki)

  • Panu Kovanen

    (Helsinki University Central Hospital and University of Helsinki)

  • Marjut Leidenius

    (Helsinki University Central Hospital)

  • Tuomo Meretoja

    (Helsinki University Central Hospital)

  • Katja Hukkinen

    (Helsinki University Central Hospital)

  • Outi Monni

    (University of Helsinki)

  • Jeroen Pouwels

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

  • Biswajyoti Sahu

    (University of Helsinki)

  • Johanna Mattson

    (University of Helsinki & Helsinki University Hospital)

  • Heikki Joensuu

    (University of Helsinki & Helsinki University Hospital)

  • Päivi Heikkilä

    (Helsinki University Central Hospital and University of Helsinki)

  • Laura L. Elo

    (University of Turku and Åbo Akademi University)

  • Ciara Metcalfe

    (Genentech Inc.)

  • Melissa R. Junttila

    (Genentech Inc.)

  • Olli Ikkala

    (Aalto University School of Science
    Aalto University School of Chemical Engineering)

  • Juha Klefström

    (University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki)

Abstract

Breast cancer is now globally the most frequent cancer and leading cause of women’s death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.

Suggested Citation

  • Pauliina M. Munne & Lahja Martikainen & Iiris Räty & Kia Bertula & Nonappa & Janika Ruuska & Hanna Ala-Hongisto & Aino Peura & Babette Hollmann & Lilya Euro & Kerim Yavuz & Linda Patrikainen & Maria S, 2021. "Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27220-9
    DOI: 10.1038/s41467-021-27220-9
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