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

• Published in: Nature communications Vol. 12; no. 1; pp. 6967 - 17
• Main Authors: Munne, Pauliina M., Martikainen, Lahja, Räty, Iiris, Bertula, Kia, Nonappa, Ruuska, Janika, Ala-Hongisto, Hanna, Peura, Aino, Hollmann, Babette, Euro, Lilya, Yavuz, Kerim, Patrikainen, Linda, Salmela, Maria, Pokki, Juho, Kivento, Mikko, Väänänen, Juho, Suomi, Tomi, Nevalaita, Liina, Mutka, Minna, Kovanen, Panu, Leidenius, Marjut, Meretoja, Tuomo, Hukkinen, Katja, Monni, Outi, Pouwels, Jeroen, Sahu, Biswajyoti, Mattson, Johanna, Joensuu, Heikki, Heikkilä, Päivi, Elo, Laura L., Metcalfe, Ciara, Junttila, Melissa R., Ikkala, Olli, Klefström, Juha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/51; 14/19; 38/39; 38/91; 45/90; 631/67/1347; 631/67/70; 64/60; 692/308/2778; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Case-Control Studies; Cell Line, Tumor; Cinnamates - pharmacology; Collagen - chemistry; Collagen - pharmacology; Compressive properties; Drug Combinations; Drug resistance; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenetics; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Extracellular matrix; Female; Fulvestrant - pharmacology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genotype & phenotype; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Indazoles - pharmacology; Laminin - chemistry; Laminin - pharmacology; Mammary Glands, Human - drug effects; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Mechanotransduction, Cellular - genetics; multidisciplinary; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Phenotypes; Proteoglycans - chemistry; Proteoglycans - pharmacology; Receptors; Scaffolds; Science; Science (multidisciplinary); Signaling; Stiffness; Tamoxifen - pharmacology; Therapeutic applications; Tissue Culture Techniques; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27220-9

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. Reliable luminal estrogen receptor (ERα+) 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 ERα expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.