Decreased PRC2 activity supports the survival of basal-like breast cancer cells to cytotoxic treatments

Evangelos Prokakis,Joanna Napp,Christian Dullin,Maria Wiese,Harriet Wikman,Marcel Werner,Taras Velychko,Florian Wegwitz,Katharina Jannasch,Lukas C Müller-Kirschbaum,Christof M Kramm,Frauke Alves,Iga K Mieczkowska,Geske E Schmidt,Garyfallia Pantelaiou-Prokaki,Klaus Pantel,Madhobi Sen

doi:10.1038/s41419-021-04407-y

Abstract

Breast cancer (BC) is the most common cancer occurring in women but also rarely develops in men. Recent advances in early diagnosis and development of targeted therapies have greatly improved the survival rate of BC patients. However, the basal-like BC subtype (BLBC), largely overlapping with the triple-negative BC subtype (TNBC), lacks such drug targets and conventional cytotoxic chemotherapies often remain the only treatment option. Thus, the development of resistance to cytotoxic therapies has fatal consequences. To assess the involvement of epigenetic mechanisms and their therapeutic potential increasing cytotoxic drug efficiency, we combined high-throughput RNA- and ChIP-sequencing analyses in BLBC cells. Tumor cells surviving chemotherapy upregulated transcriptional programs of epithelial-to-mesenchymal transition (EMT) and stemness. To our surprise, the same cells showed a pronounced reduction of polycomb repressive complex 2 (PRC2) activity via downregulation of its subunits Ezh2, Suz12, Rbbp7 and Mtf2. Mechanistically, loss of PRC2 activity leads to the de-repression of a set of genes through an epigenetic switch from repressive H3K27me3 to activating H3K27ac mark at regulatory regions. We identified Nfatc1 as an upregulated gene upon loss of PRC2 activity and directly implicated in the transcriptional changes happening upon survival to chemotherapy. Blocking NFATc1 activation reduced epithelial-to-mesenchymal transition, aggressiveness, and therapy resistance of BLBC cells. Our data demonstrate a previously unknown function of PRC2 maintaining low Nfatc1 expression levels and thereby repressing aggressiveness and therapy resistance in BLBC.

Highlights

Breast cancer (BC) is the most common cancerous disease in women with over 2.2 million new cases in 2020 worldwide, and represents 1% of all male malignancies [1, 2]
We concluded that the reduction of therapy (CAF) gain stem cell traits and epithelial-to-mesenchymal transition (EMT) properties in vitro polycomb repressive complex 2 (PRC2) levels was associated with the survival to cytotoxic therapies
We asked whether the identified phosphamide, 15.6 ng/ml doxorubicin, and 312.5 ng/ml 5-FU, reduction of PRC2 activity could directly mediate WAP-T tumor corresponding to the 1/32 dilution of the therapy previously cell survival to cytotoxic therapies by de-repressing specific gene utilized in Jannasch et al [31], was identified as the most expression programs involved in tumor aggressiveness and/or appropriate setting (Fig. 1A and B)

Summary

Introduction

Breast cancer (BC) is the most common cancerous disease in women with over 2.2 million new cases in 2020 worldwide, and represents 1% of all male malignancies [1, 2]. The mortality of BC patients has significantly decreased over the past decades, mostly because of early diagnosis improvements and the development of several targeted therapies. Despite intensive efforts to combat the disease, BC remains the first cancer-related cause of death among women. BC recurrence rate fluctuates between 5% and 10% within 10 years [3,4,5,6]. Around 25% of BC patients still develop resistant and/or metastatic lesions with an unfavorable outcome [7]. There is an urgent need for improved treatment options efficiently targeting resistant relapses and metastases

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Conclusion