Compressive stress-mediated p38 activation required for ER\u03b1\u2009+\u2009phenotype in breast cancer

Pauliina Munne ,Iiris Räty,Päivi Heikkilä,Juho Väänänen,Juha Klefström,Katja Hukkinen,Laura L Elo,Mikko Kivento,Outi Monni,Melissa R Junttila,Liina Nevalaita,Hanna Ala-Hongisto,Tuomo J Meretoja ,Olli Ikkala,Lahja Martikainen,Marjut Leidenius,Aino Peura,Panu E Kovanen ,Nonappa Nonappa ,Tomi Suomi,Heikki Joensuu,Maria Salmela,Babette Hollmann,Minna Mutka,Lilya Euro,Kia Bertula,Johanna Mattson,Ciara Metcalfe,Jeroen Pouwels,Kerim Yavuz,Janika Ruuska,Linda Patrikainen,Biswajyoti Sahu,Juho Pokki

doi:10.1038/s41467-021-27220-9

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.

Highlights

Breast cancer is globally the most frequent cancer and leading cause of women’s death
Stable ERα expression has been reported in patient-derived xenograft (PDX) models, especially in tumor cells introduced via intraductal transplantations[8,9] and these findings have suggested a strong microenvironment-dependent dynamic component in the regulation of ERα expression
We show that the physiological stiffness of the culture matrix and, apparently, breast tissue microenvironment is coupled via the p38/stress-activated protein kinases-mediated stress pathway and the H3K27me3-dependent epigenetic chromatin remodeling to ERα expression in luminal breast epithelial cells and cancer cells

Summary

Introduction

Breast cancer is globally the most frequent cancer and leading cause of women’s death. Stable ERα expression has been reported in patient-derived xenograft (PDX) models, especially in tumor cells introduced via intraductal transplantations[8,9] and these findings have suggested a strong microenvironment-dependent dynamic component in the regulation of ERα expression. There are few new ex vivo models for ERα + breast epithelial cells available[13,14,15], the current data provide scant mechanistic insight into the culture parameters necessary for hormone receptor expression. We show that the physiological stiffness of the culture matrix and, apparently, breast tissue microenvironment is coupled via the p38/stress-activated protein kinases-mediated stress pathway and the H3K27me3-dependent epigenetic chromatin remodeling to ERα expression in luminal breast epithelial cells and cancer cells. We show that ERα expression is not hardwired to luminal cell identity in breast cancer, but rather, it is an independent extracellular matrix stiffness regulated cellular pathway

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Conclusion