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

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.

HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer

“…In a recent study, we leveraged the WAP-T mammary carcinoma mouse model system (parental G-2 cells; pG-2) to study the mechanisms underlying resistance to combined cytotoxic chemotherapy (cyclophosphamide, adriamycin, 5-fluorouracil; short CAF) and confirmed the enrichment of EMT-associated features along with the disease progression (Fig. 1 A), [ 17 , 18 ]. Hence, we sought to validate the activation of the EMT transcriptional program in a human BLBC cell line (HCC1806) upon different conventional chemotherapy treatments (CAF, cisplatin and paclitaxel).…”

“…Previous studies of our group and others identified that epigenetic mechanisms are frequently involved in the EMT transcriptomic program induction of cancer cells [ 18 – 22 ]. To better understand factors that could be responsible for the transcriptional changes observed in BLBC cells upon chemotherapy treatment and to identify potentially druggable upregulated epigenetic effectors, we re-analyzed the mRNA-seq data of our previous study [ 18 ]. We identified 76 differentially regulated epigenetic factors (log2FC ≥ l0.7l, p -adj < 0.05), of which only 9 were significantly upregulated (Fig.…”

“…5 B). The increased chemotherapy efficiency was particularly visible in one resistant variant of the pG-2 cells (rG-2) [ 18 ], where siHdac8 alone had no significant effect on the cell growth (Fig. 5 C).…”

“…We recently leveraged the WAP-T mammary carcinoma mouse model to get insights into transcriptional mechanisms underlying the survival of BLBC cells to a CAF chemotherapy [ 14 ]. We thereby demonstrated that the loss of PRC2 repressive activity can drive aggressive BLBC tumor cell phenotypes by promoting NFATc1 expression [ 18 ]. In the present study, we analyzed RNA-seq and ChIP-seq data from the same model and identified HDAC8 as an upregulated epigenetic factor supporting BLBC cell chemotherapy resistance by repressing the epithelial differentiation program, and with a potential as a drug target.…”

ROBO3s: a novel ROBO3 short isoform promoting breast cancer aggressiveness

“…Recently, we treated WAP-T tumors with a combination of Cyclophosphamide/Adriamycin/5-fluorouracil (short CAF) and observed that a single cycle of this treatment is not able to eradicate the disease [ 16 ]. Notably, recurrences recapitulated the human situation, showing increased aggressiveness and dissemination properties, pronounced epithelial-to-mesenchymal transition (EMT), and cancer stem cell (CSC) traits [ 17 , 18 ].…”