IntroductionThe estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.MethodsPreclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.ResultsTreatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.ConclusionOur results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.

Drosophila adults, when placed into a novel open-field arena, initially exhibit an elevated level of activity followed by a reduced stable level of spontaneous activity and spend a majority of time near the arena edge, executing motions along the walls. In order to determine the environmental features that are responsible for the initial high activity and wall-following behavior exhibited during exploration, we examined wild-type and visually impaired mutants in arenas with different vertical surfaces. These experiments support the conclusion that the wall-following behavior of Drosophila is best characterized by a preference for the arena boundary, and not thigmotaxis or centrophobicity. In circular arenas, Drosophila mostly move in trajectories with low turn angles. Since the boundary preference could derive from highly linear trajectories, we further developed a simulation program to model the effects of turn angle on the boundary preference. In an hourglass-shaped arena with convex-angled walls that forced a straight versus wall-following choice, the simulation with constrained turn angles predicted general movement across a central gap, whereas Drosophila tend to follow the wall. Hence, low turn angled movement does not drive the boundary preference. Lastly, visually impaired Drosophila demonstrate a defect in attenuation of the elevated initial activity. Interestingly, the visually impaired w1118 activity decay defect can be rescued by increasing the contrast of the arena's edge, suggesting that the activity decay relies on visual detection of the boundary. The arena boundary is, therefore, a primary object of exploration for Drosophila.

Estrogen receptor (ERα) signaling plays a key role in hormonal cancer progression. ERα is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERα signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERα target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERα -mediated epigenetic pathway could play a vital role in ERα driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERα driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERα signaling potentiates epigenetic changes in cancer cells via histone modifications.

Estrogen receptor alpha (ERα) is implicated in the initiation and progression of breast cancer and its transcription depends on the modulation of epigenetic changes at target gene promoters via coregulators. There is a critical need to understand the molecular mechanism(s) by which deregulation of epigenetic changes occurs during breast cancer progression. The ERα coregulator PELP1 plays an important role in ERα signaling and is a proto-oncogene with aberrant expression in breast cancer. PELP1 interacts with histones and may be a reader of chromatin modifications. We profiled PELP1's epigenetic interactome using a histone peptide array. Our results show that PELP1 recognizes histones modified by arginine and lysine dimethylation. PELP1 functionally interacts with the arginine methyltransferase CARM1 and their interaction is enhanced by ERα. PELP1-CARM1 interactions synergistically enhance ERα transactivation. Chromatin immunoprecipitation assays revealed that PELP1 alters histone H3 arginine methylation status at ERα target gene promoters. Pharmacological inhibition or small interfering RNA knockdown of CARM1 substantially reduced PELP1 oncogenic functions. The critical role of PELP1 status in modulating arginine methylation status was also observed through in vivo studies where PELP1 knockdown mediated decreased tumorigenesis correlated with decreased arginine dimethylation. Further, immunohistochemical analysis of human breast tumor tissues revealed co-overexpression of PELP1 and CARM1 in a subset of ERα-positive breast tumors. Our findings show PELP1 is a reader of histone arginine methyl modifications and deregulation promotes tumor proliferation via epigenetic alterations at ERα target promoters. Targeting these epigenetic alterations through inhibition of PELP1 and the arginine methyltransferases could be a promising cancer therapeutic.

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The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly with ER and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.DOI: http://dx.doi.org/10.7554/eLife.26857.001

The Schizotypal Ambivalence Scale (SAS) is a 19-item revision of the Intense Ambivalence Scale, which was designed to identify ambivalence described by Meehl as characteristic of schizotypy and schizophrenia. The present study examined the psychometric properties of the SAS in a sample of 997 college students. The study also provided preliminary evidence regarding the concurrent validity of the measure for identifying schizophreniclike symptoms and other forms of psychopathology in a sample of 131 students. The SAS has good internal consistency reliability (.84) and correlates moderately with other psychometric indices of schizotypy. High SAS scores were associated with schizotypal, schizoid, and paranoid symptoms, and with poorer overall functioning (after the removal of variance associated with other schizotypy scales), but were not associated with major depressive disorder or ratings of substance use and abuse.

, glutamic acid-and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or c-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. Cell Death and Differentiation (2014) 21, 1409-1418; doi:10.1038/cdd.2014.55; published online 2 May 2014 p53 is considered as the guardian of genomic integrity and has an important role in initiating cellular response to various genomic stresses such as cell cycle arrest, senescence, DNA repair and apoptosis.1,2 Loss of p53 or mutations in p53 is observed in 450% of the cases of all cancers.3-5 Stabilization of p53 upon genomic stress and activation of its transcription functions are vital for its central role in the DNA damage/ genomic stress response and in its tumor-suppressive functions.6,7 Upon genomic stress, p53 is stabilized and activated because of a decreased interaction with its E3-ligase MDM2.8 Activated p53 then upregulates expression of target genes, such as p21/WAF1, GADD45, PUMA and NOXA, all of which are important in the cellular decisions for cell cycle arrest or apoptosis. Post-translational modifications of p53, including phosphorylation, acetylation, ubiquitinylation and methylation, 10-12 and interactions with several cofactors 13,14 have a critical role in the p53-mediated transcriptional response to the DNA damage response (DDR). Proline-, glutamic acid-and leucine-rich protein-1 (PELP1), a large multi-domain protein, modulates a number of biological processes and several pathways including estrogen signaling, and cancer progression. 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.25 PELP1 localizes to the nucleolus and has an important role in ribosomal biogenesis.26 PELP1 signaling is also implicated in apoptosis and differentiation, and PELP1 functions as a coactivator of RXR homodimers and RXR-PPAR heterodimers.27 Although PELP1's role in both cell proliferation and differentiation is evident, it is not known how PELP1 would affect p53-mediated DDR functions and whether PELP1 status would affect sensitivity to various genomic stresses.In this study,...