Abstract
Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. Withaferin A (WA) is a plant derived steroidal lactone which holds promise as a therapeutic agent for treatment of breast cancer (BC). We determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines, following 72h treatment to a sub-cytotoxic concentration of WA. In contrast to the DNA demethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of MDA-MB-231 cells rather tackles an epigenetic cancer network through gene-specific DNA hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Gene expression and pathway enrichment analysis further reveals epigenetic suppression of multiple cancer hallmarks associated with cell cycle regulation, cell death, cancer cell metabolism, cell motility and metastasis. Remarkably, DNA hypermethylation of corresponding CpG sites in PLAU, ADAM8, TNSF12, GSTM1 and ME3 genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ESR)/progesterone receptor (PR) status in primary BC tumors. Moreover, upon comparing differentially methylated WA responsive target genes with DNA methylation changes in different clinical subtypes of breast cancer patients in the cancer genome atlas (TCGA), we found that WA silences HER2/PR/ESR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks, with an improved therapeutic sensitivity. In this respect, WA may represent a novel and attractive phyto-pharmaceutical for TNBC treatment.
Highlights
Breast cancer (BC), which remains the leading cause of cancer related deaths in women, is a highly heterogeneous disease
First we assessed whether strong suppression of metastasis and invasive properties of Withaferin A (WA) in triple negative MDA-MB-231 breast cancer cells observed upon 72 h exposure of MDA-MB-231 cells to sub-cytotoxic concentrations of WA (700 nM) can be explained by WA dependent epigenetic effects on DNA methylation [34]
Genome-wide changes in DNA methylation following WA treatment were quantified by Infinium Human Methylation450 BeadChip arrays in aggressive metastatic MDA-MB-231 cells and weakly metastatic MCF-7 cells
Summary
Breast cancer (BC), which remains the leading cause of cancer related deaths in women, is a highly heterogeneous disease. In a series of articles, Perou et al and Sorlie et al have identified five intrinsic molecular BC subtypes based on distinct gene expression patterns: “Normal breast-like”, estrogen www.impactjournals.com/oncotarget receptor α positive (ESR+) “Luminal A” and “Luminal B”, and ER negative (ESR-) “Receptor tyrosine-protein kinase erbB-2 amplification positive (HER2+)/ESR-“ and “Basal-like” subtypes [1, 2]. Besides changes in gene expression, extensive DNA methylation alterations contribute to BC initiation and malignant transformation [5,6,7,8]. DNA methylation aids the risk stratification of TNBC patients, and due to its dynamic nature opens a new window of therapeutic opportunities in this highly aggressive form of BC
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