Project description:This SuperSeries is composed of the following subset Series: GSE28006: The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [mRNA profiling] GSE28007: The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [ChIP-seq] Refer to individual Series
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:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with EGF. The hypothesis tested was that PBX1 is essential for EGF signaling in ERa positive breast cancer cells.
Project description:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with estradiol. The hypothesis tested was that PBX1 is essential for estrogen signaling in ERa positive breast cancer cells.
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.
Project description:Estrogen Receptor alpha (ERa) is the main driver of luminal breast cancer development and progression, and represents the main drug target in patient care. ERa chromatin binding has been extensively studied in breast cancer cell lines and a number of human tumors, often focused on differential binding patterns between groups or conditions. However, little is known about the inter-tumor heterogeneity of ERa chromatin action. Here, we use a large set of ERa ChIP-seq data from 70 ERa+ breast cancers (40 women & 30 men) to explore general inter-patient heterogeneity in ERa DNA binding in breast cancers. We found a total universe of 84,565 and 101,653 ERa sites in females and males respectively, with merely 1.2% and 5% of sites shared in at least half of the tumors analyzed, reflecting a high level of inter-patient heterogeneity. This heterogeneity was found to be most variable at putative enhancers as opposed to promoter regions, potentially reflecting a level of functional redundancy in enhancer action. Interestingly, commonly shared ERa sites showed the highest estrogen-driven enhancer activity, as determined using a massive parallel reporter assay, and were most-engaged in long-range chromatin interactions. In addition, the most-commonly shared ERa-occupied enhancers were found enriched for breast cancer risk SNP loci. We experimentally illustrate such SNVs can impact chromatin binding potential for ERa and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we could confirm these variations to associate with differences in expression for the target gene. Cumulatively, our data reveal a natural hierarchy of ERa-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ERa landscape, with the most-common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
Project description:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with estradiol. The hypothesis tested was that PBX1 is essential for estrogen signaling in ERa positive breast cancer cells. Total RNA was obtained from MCF7 cells treated with siRNA directed at PBX1 or an siControl for 72h. Cells were then stimulated with estradiol (E2) for 3h prior to RNA extraction.
Project description:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with EGF. The hypothesis tested was that PBX1 is essential for EGF signaling in ERa positive breast cancer cells. Total RNA was obtained from MCF7 cells treated with siRNA directed at PBX1 or an siControl for 72h. Cells were then stimulated with estradiol (EGF) for 3h prior to RNA extraction.
