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

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 Salmela, Juho Pokki, Mikko Kivento, Juho Väänänen, Tomi Suomi, Liina Nevalaita, Minna Mutka, Marjut LeideniusTuomo Meretoja, Katja Hukkinen, Outi Monni, Jeroen Pouwels, Biswajyoti Sahu, Johanna Mattson, Heikki Joensuu, Laura L. Elo, Ciara Metcalfe, Melissa R. Junttila, Olli Ikkala, Juha Klefström

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
Article number6967
Number of pages17
JournalNature Communications
Volume12
DOIs
Publication statusPublished - Dec 2021
Publication typeA1 Journal article-refereed

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