Abstract
BackgroundBasal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. Resistance to chemotherapy is the main cause of treatment failure in BLBC. Therefore, novel therapeutic strategies counteracting the gain of aggressiveness underlying therapy resistance are urgently needed. The epithelial-to-mesenchymal transition (EMT) has been established as one central process stimulating cancer cell migratory capacity but also acquisition of chemotherapy-resistant properties. In this study, we aimed to uncover epigenetic factors involved in the EMT-transcriptional program occurring in BLBC cells surviving conventional chemotherapy.ResultsUsing whole transcriptome data from a murine mammary carcinoma cell line (pG-2), we identified upregulation of Hdac4, 7 and 8 in tumor cells surviving conventional chemotherapy. Subsequent analyses of human BLBC patient datasets and cell lines established HDAC8 as the most promising factor sustaining tumor cell viability. ChIP-sequencing data analysis identified a pronounced loss of H3K27ac at regulatory regions of master transcription factors (TFs) of epithelial phenotype like Gata3, Elf5, Rora and Grhl2 upon chemotherapy. Interestingly, impairment of HDAC8 activity reverted epithelial-TFs levels. Furthermore, loss of HDAC8 activity sensitized tumor cells to chemotherapeutic treatments, even at low doses.ConclusionThe current study reveals a previously unknown transcriptional repressive function of HDAC8 exerted on a panel of transcription factors involved in the maintenance of epithelial cell phenotype, thereby supporting BLBC cell survival to conventional chemotherapy. Our data establish HDAC8 as an attractive therapeutically targetable epigenetic factor to increase the efficiency of chemotherapeutics.Graphical abstract
Highlights
Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer
BLBC cells surviving chemotherapy upregulates HDAC4, HDAC7 and Histone deacetylation 8 (HDAC8) Previous studies of our group and others identified that epigenetic mechanisms are frequently involved in the epithelial-to-mesenchymal transi‐ tion (EMT) transcriptomic program induction of cancer cells [18,19,20,21,22]
In line with our results in vitro, HDAC8 was the only member of the three selected Histone deacetylases (HDACs) whose expression significantly correlated with a poor BLBC patient prognosis (Fig. 2G and Additional file 1: Fig. S1H)
Summary
Basal-like breast cancer (BLBC) is one of the most aggressive malignant diseases in women with an increased metastatic behavior and poor prognosis compared to other molecular subtypes of breast cancer. TNBCs distinguish themselves from other histological BC subtypes by the absence of estrogen receptor (ER), progesterone receptor (PR) expression and human epidermal growth factor 2 (HER2) gene amplification, as assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively [2]. This characteristic makes the group of TNBC lesions largely overlapping with the basal-like (BLBC) and to a much lower extend with normal-like molecular subtypes [1, 3], thereby rendering this type of malignancies insensitive to hormone and anti-HER2-targeted therapies. Patients with relapses or residual disease have a high probability to develop metastatic outgrowth and subsequently succumb to their disease [2]
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