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

Pauliina M. Munne; Lahja Martikainen; Iiris Räty; Kia Bertula; null 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

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 KovanenMarjut 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Scientific › peer-review

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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.

Original language	English
Article number	6967
Pages (from-to)	1-17
Number of pages	17
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27220-9
Publication status	Published - 29 Nov 2021
MoE publication type	A1 Journal article-refereed

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Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancerFinal published version, 29.5 MBLicence: CC BY

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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., ... Klefström, J. (2021). Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer. Nature Communications, 12(1), 1-17. Article 6967. https://doi.org/10.1038/s41467-021-27220-9

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title = "Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer",

abstract = "Breast cancer is now globally the most frequent cancer and leading cause of women{\textquoteright}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.",

author = "Munne, {Pauliina M.} and Lahja Martikainen and Iiris R{\"a}ty and Kia Bertula and Nonappa and Janika Ruuska and Hanna Ala-Hongisto and Aino Peura and Babette Hollmann and Lilya Euro and Kerim Yavuz and Linda Patrikainen and Maria Salmela and Juho Pokki and Mikko Kivento and Juho V{\"a}{\"a}n{\"a}nen and Tomi Suomi and Liina Nevalaita and Minna Mutka and Panu Kovanen and Marjut Leidenius and Tuomo Meretoja and Katja Hukkinen and Outi Monni and Jeroen Pouwels and Biswajyoti Sahu and Johanna Mattson and Heikki Joensuu and P{\"a}ivi Heikkil{\"a} and Elo, {Laura L.} and Ciara Metcalfe and Junttila, {Melissa R.} and Olli Ikkala and Juha Klefstr{\"o}m",

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Munne, PM, 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, LL, Metcalfe, C, Junttila, MR, 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

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T1 - Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer

AU - Munne, Pauliina M.

AU - Martikainen, Lahja

AU - Räty, Iiris

AU - Bertula, Kia

AU - Nonappa, null

AU - Ruuska, Janika

AU - Ala-Hongisto, Hanna

AU - Peura, Aino

AU - Hollmann, Babette

AU - Euro, Lilya

AU - Yavuz, Kerim

AU - Patrikainen, Linda

AU - Salmela, Maria

AU - Pokki, Juho

AU - Kivento, Mikko

AU - Väänänen, Juho

AU - Suomi, Tomi

AU - Nevalaita, Liina

AU - Mutka, Minna

AU - Kovanen, Panu

AU - Leidenius, Marjut

AU - Meretoja, Tuomo

AU - Hukkinen, Katja

AU - Monni, Outi

AU - Pouwels, Jeroen

AU - Sahu, Biswajyoti

AU - Mattson, Johanna

AU - Joensuu, Heikki

AU - Heikkilä, Päivi

AU - Elo, Laura L.

AU - Metcalfe, Ciara

AU - Junttila, Melissa R.

AU - Ikkala, Olli

AU - Klefström, Juha

N1 - | openaire: EC/H2020/742829/EU//DRIVEN | openaire: EC/H2020/847912/EU//RESCUER

PY - 2021/11/29

Y1 - 2021/11/29

N2 - 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.

AB - 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.

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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PreClinica: Novel Preclinical Model for Breast Cancer Theraphy

HYBER: The Academy of Finland's Centre of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials research (2014-2019)

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Finnish researchers developed mini-breast cancer as new weapon against most common type of breast cancer

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

Abstract

UN SDGs

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Projects

PreClinica: Novel Preclinical Model for Breast Cancer Theraphy

HYBER: The Academy of Finland's Centre of Excellence in Molecular Engineering of Biosynthetic Hybrid Materials research (2014-2019)

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OtaNano - Nanomicroscopy Center

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University of Helsinki: Finnish Researchers Developed Mini-Breast Cancer as a New Weapon Against the Most Common Type of Breast Cancer

Finnish researchers developed mini-breast cancer as new weapon against most common type of breast cancer

Cite this