High-entropy alloys are equiatomic, multi-element systems that can crystallize as a single phase, despite containing multiple elements with different crystal structures. A rationale for this is that the configurational entropy contribution to the total free energy in alloys with five or more major elements may stabilize the solid-solution state relative to multiphase microstructures. We examined a five-element high-entropy alloy, CrMnFeCoNi, which forms a single-phase face-centered cubic solid solution, and found it to have exceptional damage tolerance with tensile strengths above 1 GPa and fracture toughness values exceeding 200 MPa·m(1/2). Furthermore, its mechanical properties actually improve at cryogenic temperatures; we attribute this to a transition from planar-slip dislocation activity at room temperature to deformation by mechanical nanotwinning with decreasing temperature, which results in continuous steady strain hardening.

Two subtypes of the estrogen receptor (ER), ER␣ and ER␤, mediate the actions of estrogens, and although 70% of human breast cancers express ER␤ along with ER␣, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ER␤, along with their endogenous ER␣, and have examined the effects of ER␤ and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ER␤ had diverse effects on gene expression, enhancing or counteracting ER␣ regulation for distinct subsets of estrogen target genes. Strikingly, ER␤ in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that reproductive physiology and development, and in the functioning of numerous nonreproductive tissues as well. Estrogen hormones also influence the growth of various cancers (1), including breast and endometrial cancers. Although estrogens were originally thought to signal through only one form of estrogen receptor (ER), the complexity of estrogen physiology was compounded when a second form of the ER (termed ER␤, ESR2) was cloned (2, 3). Since then, much effort has gone into investigating the specific roles of the two receptor subtypes in diverse estrogen target tissues (4 -7).Although ER␤ is normally coexpressed with ER␣ in many tissue types, and the majority of human breast cancers express ER␤ along with ER␣ (8 -10), it is not fully known how the presence of both receptors and their relative levels control cellular responses to estrogen. These two transcription factors have a similar domain structure and very similar DNA binding domains, but have substantial differences in their ligand binding domains and especially in their N-terminal activation function regions (1, 11). Examination of their separate activities in osteosarcoma cells indicated distinct as well as overlapping gene regulatory activities (12, 13). Because these receptors are able to heterodimerize when present in the same cell (14), their joint actions and possible comodulatory effects on gene regulation are issues of importance.Although it is well documented that ER␣-positive breast cancer cells show enhanced proliferation in response to estrogen (15, 16), the manner in which ER␤ impacts estrogen mitogenicity and the changes in gene expression that underlie these effects are less clear, although several reports support the role of ER␤ as a negative regulator of ER␣ (17)(18)(19).To better understand the role of ER␤ in influencing estrogen action, we have used adenoviral gene delivery of ER␤ and gene expression microarray analyses to investigate gene regulatory effects of ER␤ in breast cancer cells expressing ER␣, as well as to distill the information into gene networks and pathways responsible for controlling estrogen activities. Our results indicate that ER␤ can modulate ER␣ gene expression in both an enhancing and a suppressing fashion, and...

Key Points Dnmt3a ablation in HSCs predisposes mice to develop a spectrum of myeloid and lymphoid malignancies. Dnmt3a-KO-derived myeloid malignancies and T-cell acute lymphocytic leukemia/lymphoma show distinct methylation aberrations.

The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/ antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E 2 ) or raloxifene in ERA-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERA and reversed by E 2 or ICI 182,780. Introduction of ERB into MCF-7 cells reverses tamoxifen action on f75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifenstimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy. (Cancer Res 2006; 66(14): 7334-40)

Estrogen receptors alpha and beta (ERalpha and ERbeta) mediate the actions of estrogens in a variety of normal and cancer target cells. Estrogens differ in their preference for these ERs, and many phytoestrogens bind preferentially to ERbeta. To investigate how phytoestrogens such as genistein impact ER-regulated gene expression, we used adenoviral gene delivery of ERbeta coupled with ERalpha depletion with small interfering RNA to generate human breast cancer (MCF-7) cells expressing four complements of ERalpha and ERbeta. We examined the dose-dependent effects of genistein on genome-wide gene expression by DNA microarrays and monitored the recruitment of ERs and coregulators to responsive regions of estrogen-regulated genes. At a low (6 nm) concentration, genistein regulated gene expression much more effectively in cells coexpressing ERalpha and ERbeta than in cells expressing ERalpha alone, whereas at high concentration (300 nm), genistein induced transcriptome changes very similar to that of 17beta-estradiol. We demonstrate that ERbeta is preferentially activated by genistein and is recruited to estrogen-responsive genomic sites and that differential occupancy of ERalpha and ERbeta by genistein and 17beta-estradiol in turn influences the recruitment patterns of coregulators such as steroid receptor coactivator 3 (SRC3) and receptor-interacting protein 140 (RIP140). Our observations indicate that genistein is a potency-selective ligand for gene expression regulation by ERalpha and ERbeta and that the ability of ERalpha and ERbeta to serve as determinants of gene expression is greatly influenced by the nature of the ligand, by ligand dose, and by the differential abilities of ligand-ER complexes to recruit different coregulators at ER binding sites of hormone-regulated genes.

No abstract

Estrogen receptors ERalpha and ERbeta, members of the nuclear receptor superfamily, exert profound effects on the gene expression and biological response programs of their target cells. Herein, we explore the dynamic interplay between these two receptors in their selection of chromatin binding sites when present separately or together in MCF-7 breast cancer cells. Treatment of cells (containing ERalpha only, ERbeta only, or ERalpha and ERbeta) with estradiol or ER subtype-selective ligands was followed by chromatin immunoprecipitation analysis with a custom-designed tiling array for ER binding sites across the genome to examine the effects of ligand-occupied and unoccupied ERalpha and ERbeta on chromatin binding. There was substantial overlap in binding sites for these estradiol-liganded nuclear receptors when present alone, but many fewer sites were shared when both ERs were present. Each ER restricted the binding site occupancy of the other, with ERalpha generally being dominant. Binding sites of both receptors were highly enriched in estrogen response element motifs, but when both ERs were present, ERalpha displaced ERbeta, shifting it into new sites less enriched in estrogen response elements. Binding regions of the two ERs also showed differences in their enrichments for other transcription factor binding motifs. Studies with ER subtype-specific ligands revealed that it was the liganded subtype that principally determined the spectrum of chromatin binding. These findings highlight the dynamic interplay between the two ERs in their selection of chromatin binding sites, with competition, restriction, and site shifting having important implications for the regulation of gene expression by these two nuclear receptors.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most PLOS GENETICS