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; Juha Klefström

doi:10.1038/s41467-021-27220-9

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

Nat Commun. 2021 Nov 29;12(1):6967. doi: 10.1038/s41467-021-27220-9.

Authors

Pauliina M Munne¹, Lahja Martikainen^#², Iiris Räty^#¹, Kia Bertula², Nonappa^{2

3}, Janika Ruuska¹, Hanna Ala-Hongisto¹, Aino Peura¹, Babette Hollmann¹, Lilya Euro⁴, Kerim Yavuz⁵, Linda Patrikainen¹, Maria Salmela¹, Juho Pokki⁶, Mikko Kivento⁷, Juho Väänänen⁷, Tomi Suomi⁸, Liina Nevalaita¹, Minna Mutka⁹, Panu Kovanen⁹, Marjut Leidenius¹⁰, Tuomo Meretoja¹⁰, Katja Hukkinen¹¹, Outi Monni⁷, Jeroen Pouwels¹, Biswajyoti Sahu⁵, Johanna Mattson¹², Heikki Joensuu¹², Päivi Heikkilä⁹, Laura L Elo⁸, Ciara Metcalfe¹³, Melissa R Junttila¹³, Olli Ikkala^{2

3}, Juha Klefström¹⁴

Affiliations

¹ Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
² Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
³ Department of Bioproducts and Biosystems, Aalto University School of Chemical Engineering, Espoo, Finland.
⁴ Research Program of Stem Cells and Metabolism, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland.
⁵ Applied Tumor Genomics Research Program, Enhancer Biology Laboratory, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ Department of Electrical Engineering and Automation, Aalto University, Espoo, Finland.
⁷ Applied Tumor Genomics Research Program, Faculty of Medicine, Oncogenomics Laboratory, University of Helsinki, Helsinki, Finland.
⁸ Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland.
⁹ Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
¹⁰ Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.
¹¹ Department of Mammography, Helsinki University Central Hospital, Helsinki, Finland.
¹² Department of Oncology, University of Helsinki & Helsinki University Hospital, Helsinki, Finland.
¹³ Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
¹⁴ Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Case-Control Studies
Cell Line, Tumor
Cinnamates / pharmacology
Collagen / chemistry
Collagen / pharmacology
Drug Combinations
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Estradiol / pharmacology
Estrogen Receptor alpha / genetics*
Estrogen Receptor alpha / metabolism
Female
Fulvestrant / pharmacology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Histones / genetics
Histones / metabolism
Humans
Indazoles / pharmacology
Laminin / chemistry
Laminin / pharmacology
Mammary Glands, Human / drug effects
Mammary Glands, Human / metabolism
Mammary Glands, Human / pathology
Mechanotransduction, Cellular / genetics*
Phenotype
Proteoglycans / chemistry
Proteoglycans / pharmacology
Tamoxifen / pharmacology
Tissue Culture Techniques
Transcriptome*
p38 Mitogen-Activated Protein Kinases / genetics*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
Cinnamates
Drug Combinations
ESR1 protein, human
Estrogen Receptor alpha
Histones
Indazoles
Laminin
Proteoglycans
Tamoxifen
matrigel
Fulvestrant
Estradiol
Collagen
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
p38 Mitogen-Activated Protein Kinases