Project description:Analysis of DNA methylation changes after prolonged exposure of triple-negative breast cancer cell lines to low doses of Panobinostat (LBH589), a pan-histone deacetylase inhibitor.
Project description:Genome-wide DNA methylation profiles for 82 triple negative breast cancer (TNBC) samples from the Swedsh Cancerome Analysis Network - Breast (SCAN-B) cohort.
Project description:Analysis of chromatin accessibility changes after prolonged exposure of triple-negative breast cancer cell lines to low doses of Panobinostat (LBH589), a pan-histone deacetylase inhibitor.
Project description:Analysis of changes in gene expression levels after after prolonged exposure of triple-negative breast cancer cell lines to low doses of Panobinostat (LBH589), a pan-histone deacetylase inhibitor.
Project description:Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and cellular phenotypes. In human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in triple-negative breast cancer (TNBC), which facilitates histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in TNBC promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3Kac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo TNBC models including patient-derived xenograft, we show that Hh signaling-orchestrated H3K27me and H3Kac interplay tailors combination epigenetic drugs in treating TNBC.
Project description:Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and cellular phenotypes. In human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in triple-negative breast cancer (TNBC), which facilitates histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in TNBC promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3Kac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo TNBC models including patient-derived xenograft, we show that Hh signaling-orchestrated H3K27me and H3Kac interplay tailors combination epigenetic drugs in treating TNBC.
Project description:Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, triple-negative is the subtype that lacks the expression of major differentiation markers (i.e. estrogen receptor [ER]), ant its high cellular plasticity results in higher aggressiveness and poor prognosis compared to other subtypes. Whether plasticity poses a vulnerability to cancer cells remains elusive. Here, we show that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer. Using a high-throughput reporter drug screen with 9,501 compounds, we identify three polo-like kinase 1 (PLK1) inhibitors as major inducers of ER protein expression and downstream activity in triple-negative breast cancer cells via the transcription factor BATF. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest and ultimately cell death. Notably, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line and patient-derived xenograft models. In addition, genes upregulated upon PLK1 inhibition are correlated with expression in normal breast tissue and confer better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition might be an alternative strategy to treat triple-negative breast cancer.
