Notes

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While ER mutations exhibited minor effects on ER genomic binding, with the exception of ligand independence, ER mutations conferred substantial differences in chromatin accessibility. Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors, including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity. SIGNIFICANCE This study demonstrates the multiple roles of mutant ER in breast cancer progression, including constant ER activity and secondary regulatory effects on gene expression and chromatin accessibility. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/81/3/539/F1.large.jpg.See related commentary by Hermida-Prado and Jeselsohn, p. 537See related article by Williams and colleagues, p. 732.Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies. ISM001-055 nmr SIGNIFICANCE This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype "BRCAness," yielding promising biomarkers, targets, and opportunities to resensitize refractory disease.See related commentary by Canman, p. 1214.The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. SIGNIFICANCE These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.Transcriptional enhancers commonly work over long genomic distances to precisely regulate spatiotemporal gene expression patterns. Dissecting the promoters physically contacted by these distal regulatory elements is essential for understanding developmental processes as well as the role of disease-associated risk variants. Modern proximity-ligation assays, like HiChIP and ChIA-PET, facilitate the accurate identification of long-range contacts between enhancers and promoters. However, these assays are technically challenging, expensive, and time-consuming, making it difficult to investigate enhancer topologies, especially in uncharacterized cell types. To overcome these shortcomings, we therefore designed LoopPredictor, an ensemble machine learning model, to predict genome topology for cell types which lack long-range contact maps. To enrich for functional enhancer-promoter loops over common structural genomic contacts, we trained LoopPredictor with both H3K27ac and YY1 HiChIP data. Moreover, the integration of several related multi-omics features facilitated identifying and annotating the predicted loops.
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