Project description:In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which genes transcription is coordinately regulated in response to steroid hormones. Here we further described that responsive TADs contain 20-100 kb-long clusters of intermingled estrogen receptor (ER) and progesterone receptor (PR) binding sites, hereafter called Hormone-Control Regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ER and PR. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters even in the absence of hormones in ER+-PR+ cells. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms integrating different signals resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors, but also as local and global genome organizers.
Project description:Heat shock protein-90 chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function towards client activity in cells remains elusive. Here, we dissected the impact of newly identified co-chaperones in higher eukaryotes, FNIP1/2 (FNIPs) and Tsc1, towards Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1 and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. Here, we provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.
Project description:Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but resistance to hormonal treatment is common. The pan-hormonal action of steroid hormonal receptors including Estrogen Receptor alpha (ERα), Androgen Receptor (AR), Progesterone Receptor (PR) and Glucocorticoid Receptor (GR) in this understudied tumor type remains wholly unexamined. This pioneering study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to patient outcome. Using chromatin immunoprecipitation coupled with massively-parallel sequencing (ChIP-seq), we characterized human MBCs for epigenetic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR and GR, along with pioneer factor FOXA1 and enhancer-enriched histone mark H3K4me1. These data were integrated with transcriptomics analyses to reveal gender-selective and genomic location-specific hormone receptor action, that are associated with survival in MBC patients.
Project description:Polycomb group (PcG) proteins are evolutionarily conserved epigenetic regulators that mediate histone modifications and suppress target gene expression, therefore establish and maintain cellular memory during development1-3. Deregulation of PcG genes is associated with various human cancers, but the mechanisms are incompletely understood4. Polyhomeotic (Ph), one of the Drosophila PcG proteins, can act as a tumor suppressor in larval imaginal discs5, 6. Cells mutant for ph overgrow and give rise to neoplastic tumors during larval development6. Here we report an intrinsic tumor-suppression mechanism mediated by the steroid hormone ecdysone in Drosophila. During metamorphosis, ecdysone transforms tumorigenic ph mutant cells into non-tumorigenic cells, thereby suppressing the malignant growth in adult flies. We demonstrate ecdysone exerts its function by inducing the expression of microRNA lethal-7 (let-7), which suppresses its target gene chinmo, to inhibit the tumorigenic growth of ph mutant cells. Furthermore, we show let-7 can also suppress the overgrowth of brain tumors in brain tumor (brat) mutant flies, indicating this intrinsic mechanism is functional in different tissues to suppress neoplastic growth. As let-7 is highly conserved among metazoans, our findings will be relevant for mechanistic studies and therapeutic applications in human cancers.