Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.
Project description:Dataset containing micro-RNA expression profiles of breast cancers at the time of endocrine resistance. It has been used to correlate micro-RNA and mRNA expressions and to identify two distinctive phenotypes with different expression of micro-RNA gens. Please note that the tumor samples are clinically quite homogeneous: all are post-menopausal ER+ve breast cancers, endocrine treated and growing on treatment. The main purpose of collecting these data was not to compare transcriptional profiles with clinical parameters, but rather to use the micro-RNA expression profiles of these clinically homogeneous tumours for (i) identifying intrinsic subgroups within endocrine resistance and (ii) for relating micro-RNA and mRNA expressions. However, the relevant clinical data was also provided as Series supplementary file (ClinicalData_AL28Jan2014.xlsx).
Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
Project description:Dataset containing whole-genome expression profiles of breast cancers at the time of endocrine resistance. It has been used to identify five distinctive phenotypes with different expression of gene clusters associated with ER-signalling, stromal rearrangement and cytokine-signalling. Pathway-focused analysis suggested individual tumours with active ER-signalling (24/55, 44%), PIK3CA-signalling (18/55, 32%), RAS (12/55, 22%) and MYC-signalling (11/55, 20%). 3 or 4 of the above pathways were simultaneously active in 6/55 (11%) cases. Results provide important information about prevalence of different mechanisms of endocrine resistance in clinical samples of breast cancer. Please note that the tumor samples are clinically quite homogeneous: all are post-menopausal ER+ve breast cancers, endocrine treated and growing on treatment. The main purpose of collecting these data was not to compare transcriptional profiles with clinical parameters, but rather to use the transcriptional profiles of these clinically homogeneous tumours for identifying intrinsic subgroups within endocrine resistance. However, the relevant clinical data was also provided as Series supplementary file (ClinicalData_AL28Jan2014.xlsx).
Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response.