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, Panu Kovanen, Marjut Leidenius, Tuomo Meretoja, Katja Hukkinen, Outi Monni, Jeroen Pouwels, Biswajyoti Sahu, Johanna Mattson, Heikki Joensuu, Päivi Heikkilä, Laura L. Elo, Ciara Metcalfe, Melissa R. Junttila, Olli Ikkala and Juha Klefström ()
Additional contact information
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
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
Juha Klefström: University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27220-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27220-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27220-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().