Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer
Monni Outi; Yavuz Kerim; Ruuska Janika; Salmela Maria; Peura Aino; Väänänen Juho; Munne Pauliina M.; Nonappa; Junttila Melissa R.; Bertula Kia; Elo Laura L.; Euro Lilya; Ikkala Olli; Pokki Juho; Hollmann Babette; Leidenius Marjut; Suomi Tomi; Joensuu Heikki; Metcalfe Ciara; Mutka Minna; Nevalaita Liina; Kivento Mikko; Ala-Hongisto Hanna; Mattson Johanna; Kovanen Panu; Heikkilä Päivi; Hukkinen Katja; Meretoja Tuomo; Pouwels Jeroen; Martikainen Lahja; Klefström Juha; Patrikainen Linda; Sahu Biswajyoti; Räty Iiris
https://urn.fi/URN:NBN:fi-fe2022012710753
Tiivistelmä
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 (ER alpha + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ER alpha-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ER alpha + breast cancer models. The ER alpha + 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 ER alpha is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ER alpha signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ER alpha 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.Reliable luminal estrogen receptor (ER alpha+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ER alpha expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.
Kokoelmat
- Rinnakkaistallenteet [19207]