Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2021-11-29
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en
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17
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Nature Communications, Volume 12, issue 1, pp. 1-17
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.Description
| openaire: EC/H2020/742829/EU//DRIVEN | openaire: EC/H2020/847912/EU//RESCUER
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Munne, P M, Martikainen, L, Räty, I, Bertula, K, Nonappa, Ruuska, J, Ala-Hongisto, H, Peura, A, Hollmann, B, Euro, L, Yavuz, K, Patrikainen, L, Salmela, M, Pokki, J, Kivento, M, Väänänen, J, Suomi, T, Nevalaita, L, Mutka, M, Kovanen, P, Leidenius, M, Meretoja, T, Hukkinen, K, Monni, O, Pouwels, J, Sahu, B, Mattson, J, Joensuu, H, Heikkilä, P, Elo, L L, Metcalfe, C, Junttila, M R, Ikkala, O & Klefström, J 2021, ' Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer ', Nature Communications, vol. 12, no. 1, 6967, pp. 1-17 . https://doi.org/10.1038/s41467-021-27220-9