Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning.

After ischemic stroke (IS), secondary injury is intimately linked to endoplasmic reticulum (ER) stress and body-brain crosstalk. Nonetheless, the underlying mechanism systemic immune disorder mediated ER stress in human IS remains unknown. In this study, 32 candidate ER stress-related genes (ERSRGs) were identified by overlapping MSigDB ER stress pathway genes and DEGs. Three Key ERSRGs (ATF6, DDIT3 and ERP29) were identified using LASSO, random forest, and SVM-RFE. IS patients with different ERSRGs profile were clustered into two groups using consensus clustering and the difference between 2 group was further explored by GSVA. Through immune cell infiltration deconvolution analysis, and middle cerebral artery occlusion (MCAO) mouse scRNA analysis, we found that the expression of 3 key ERSRGs were closely related with peripheral macrophage cell ER stress in IS and this was further confirmed by RT-qPCR experiment. These ERS genes might be helpful to further accurately regulate the central nervous system and systemic immune response through ER stress and have potential application value in clinical practice in IS.

Alkylammonium Halides for Phase Regulation and Luminescence Modulation of Cesium Copper Iodide Nanocrystals for Light-Emitting Diodes.

All-inorganic cesium copper halide nanocrystals have attracted extensive attention due to their cost-effectiveness, low toxicity, and rich luminescence properties. However, controlling the synthesis of these nanocrystals to achieve a precise composition and high luminous efficiency remains a challenge that limits their future application. Herein, we report the effect of oleylammonium iodide on the synthesis of copper halide nanocrystals to control the composition and phase and modulate their photoluminescence (PL) quantum yields (QYs). For CsCu2I3, the PL peak is centered at 560 nm with a PLQY of 47.3%, while the PL peak of Cs3Cu2I5 is located at 440 nm with an unprecedently high PLQY of 95.3%. Furthermore, the intermediate-state CsCu2I3/Cs3Cu2I5 heterostructure shows white light emission with a PLQY of 66.4%, chromaticity coordinates of (0.3176, 0.3306), a high color rendering index (CRI) of 90, and a correlated color temperature (CCT) of 6234 K, indicating that it is promising for single-component white-light-emitting applications. The nanocrystals reported in this study have excellent luminescence properties, low toxicity, and superior stability, so they are more suitable for future light-emitting applications.

Synthesis of Efficient and Stable Tetrabutylammonium Copper Halides with Dual Emissions for Warm White Light-Emitting Diodes.

In order to achieve a high color-rendering index (CRI) and low correlated color temperature (CCT) indoor lighting, single-component phosphors with broad-band dual emission are in high demand for white-light-emitting diodes (WLEDs). However, phosphors with such fluorescent properties are rare at present. Herein, we report a facile solid-state chemical method for the synthesis of single-component phosphor with broad-band emission and a large Stokes shift that can meet the requirements of future white-light sources. These new tetrabutylammonium copper halides phosphors have excellent warm white emission characteristics, and their luminescence peaks are located at 494 and 654 nm. The optimized photoluminescence (PL) quantum yield can reach 93.7 %. The typical CIE coordinate of the as-fabricated WLED is at (0.3620, 0.3731) with a CRI of 89 and low CCT of 4516 K.

Underwater endoscopic mucosal resection for rectal neuroendocrine tumors (with videos): a single center retrospective study.

BACKGROUND: Underwater endoscopic mucosal resection (UMER) is a new method of endoscopic resection to completely remove the lesion without submucosal injection. But few attempts have been carried out for rectal neuroendocrine tumors (rectal NETs). METHODS: We retrospectively investigated data on the tumor characteristics and outcomes of patients with ≤ 10 mm rectal NETs who underwent UEMR or endoscopic submucosal dissection (ESD) from January 2019 to June 2021 in our institute. RESULTS: The endoscopic resection rate was 100% in both UEMR and ESD groups. The histological complete resection rate of the UEMR group (95.5%) was lower than that of the ESD group (96.4%) with no significant difference. The average operation time, hospitalization time and operation cost of UEMR group were less than those of ESD group (P < 0.05). The incidence of postoperative abdominal pain and abdominal distention in the UEMR group was lower than that in the ESD group (P < 0.05). There was no significant difference in the incidence of delayed bleeding and perforation between the two groups. There was no local recurrence or distant metastasis in the two groups during the follow-up period. CONCLUSIONS: Both the UEMR and ESD can effectively treat ≤ 10 mm rectal NETs with invasion depth confined to the mucosa and submucosa. UEMR is superior to ESD in operation time, hospitalization time, operation cost, postoperative abdominal pain and abdominal distention.

PDGFRß is an essential therapeutic target for BRCA1-deficient mammary tumors.

BACKGROUND: Basal-like breast cancers (BLBCs) are a leading cause of cancer death due to their capacity to metastasize and lack of effective therapies. More than half of BLBCs have a dysfunctional BRCA1. Although most BRCA1-deficient cancers respond to DNA-damaging agents, resistance and tumor recurrence remain a challenge to survival outcomes for BLBC patients. Additional therapies targeting the pathways aberrantly activated by BRCA1 deficiency are urgently needed. METHODS: Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1-deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1-deficient breast cancers. RESULTS: Heterozygous germline or epithelium-specific deletion of Brca1 in p18INK4C- or p16INK4A-deficient mice activated Pdgfrß signaling, induced epithelial-to-mesenchymal transition, and led to BLBCs. Confirming this role, targeted deletion of Pdgfrß in Brca1-deficient tumor cells promoted cell death, induced mesenchymal-to-epithelial transition, and suppressed tumorigenesis. Importantly, we also found that pharmaceutical inhibition of Pdgfrß and its downstream target Pkcα suppressed Brca1-deficient tumor initiation and progression and effectively killed BRCA1-deficient cancer cells. CONCLUSIONS: Our work offers the first genetic and biochemical evidence that PDGFRß-PKCα signaling is repressed by BRCA1, which establishes PDGFRß-PKCα signaling as a therapeutic target for BRCA1-deficient breast cancers.

α-Mangostin suppresses the de novo lipogenesis and enhances the chemotherapeutic response to gemcitabine in gallbladder carcinoma cells via targeting the AMPK/SREBP1 cascades.

High rates of de novo lipid synthesis have been discovered in certain kinds of tumours, including gallbladder cancer (GBC). Unlike several other tumours, GBC is highly insensitive to standard adjuvant therapy, which makes its treatment even more challenging. Although several potential targets and signalling pathways underlying GBC chemoresistance have been revealed, the precise mechanisms are still elusive. In this study, we found that α-Mangostin, as a dietary xanthone, repressed the proliferation and clone formation ability, induced cell cycle arrest and the apoptosis, and suppressed de novo lipogenesis of gallbladder cancer cells. The underlying mechanisms might involve the activation of AMPK and, therefore, the suppression of SREBP1 nuclear translocation to blunt de novo lipogenesis. Furthermore, SREBP1 silencing by siRNA or α-mangostin enhanced the sensitivity of gemcitabine in gallbladder cancer cells. In vivo studies also displayed that MA or gemcitabine administration to nude mice harbouring NOZ tumours can reduce tumour growth, and moreover, MA administration can significantly potentiate gemcitabine-induced inhibition of tumour growth. Corroborating in vitro findings, tumours from mice treated with MA or gemcitabine alone showed decreased levels of proliferation with reduced Ki-67 expression and elevated apoptosis confirmed by TUNEL staining, furthermore, the proliferation inhibition and apoptosis up-regulation were obviously observed in MA combined with gemcitabine treatment group. Therefore, inhibiting de novo lipogenesis via targeting the AMPK/SREBP1 signalling by MA might provide insights into a potential strategy for sensitizing GBC cells to chemotherapy.

Cardioprotective effects of CYP-derived epoxy metabolites of docosahexaenoic acid involve limiting NLRP3 inflammasome activation 1.

Impaired mitochondrial function and activation of NLRP3 inflammasome cascade has a significant role in the pathogenesis of myocardial ischemia-reperfusion (IR) injury. The current study investigated whether eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or their corresponding CYP epoxygenase metabolites 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) protect against IR injury. Isolated mouse hearts were perfused in the Langendorff mode with vehicle, DHA, 19,20-EDP, EPA, or 17,18-EEQ and subjected to 30 min of ischemia and followed by 40 min of reperfusion. In contrast with EPA and 17,18-EEQ, DHA and 19,20-EDP exerted cardioprotection, as shown by a significant improvement in postischemic functional recovery associated with significant attenuation of NLRP3 inflammasome complex activation and preserved mitochondrial function. Hearts perfused with DHA or 19,20-EDP displayed a marked reduction in localization of mitochondrial Drp-1 and Mfn-2 as well as maintained Opa-1 levels. DHA and 19,20-EDP preserved the activities of both the cytosolic Trx-1 and mitochondrial Trx-2. DHA cardioprotective effect was attenuated by the CYP epoxygenase inhibitor N-(methysulfonyl)-2-(2-propynyloxy)-benzenehexanamide. In conclusion, our data indicate a differential cardioprotective response between DHA, EPA, and their active metabolites toward IR injury. Interestingly, 19,20-EDP provided the best protection against IR injury via maintaining mitochondrial function and thereby reducing the detrimental NLRP3 inflammasome responses.

Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression.

BACKGROUND: Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors. METHODS: A genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis. RESULTS: Estrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression. CONCLUSIONS: This study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER.

Tetramethylpyrazine and Astragaloside IV Synergistically Ameliorate Left Ventricular Remodeling and Preserve Cardiac Function in a Rat Myocardial Infarction Model.

Tetramethylpyrazine (TMP) and astragaloside IV (AGS-IV) are herbal ingredients that have been demonstrated in animal models to limit infarct size and protect cardiomyocytes in the acute phase of myocardial infarction (MI), yet their long-term cardioprotective effects have not been evaluated. In this study, TMP and/or AGS-IV were administrated to rats for 14 days after MI. Echocardiography revealed that the left ventricular (LV) dimensions and cardiac function were preserved in the MI rats with TMP and AGS-IV treatment, compared with untreated MI rats. Moreover, the LV dimensions and cardiac function in the MI rats with TMP and AGS-IV cotreatment were comparable with the sham-operated rats. In addition, TMP and AGS-IV synergistically inhibited LV fibrosis by attenuating MI-induced collagen deposition and elevation of transforming growth factor ß1. TMP and AGS-IV, alone or in synergy, enhanced angiogenesis in the infarcted myocardium and reduced cardiac hypertrophy of the remote myocardium after MI. Furthermore, TMP and AGS-IV mutually upregulated the expression of Sonic hedgehog (Shh), Smoothened, and Glioblastoma-2, the receptor and signal transducer of Shh signaling pathway, in the infarcted myocardium. In summary, in the circumstance of the irreversible ischemic injury, the antifibrotic, and pro-angiogenic properties of TMP and AGS-IV on the nonaffected tissues contribute to the cardioprotection in the healing phase post MI, and the cardioprotective effects are likely to be mediated through the Shh pathway.

RGB tri-luminescence in organic-inorganic zirconium halide perovskites.

Materials with two or more fluorescence features under different excitation sources have great potential in optical applications, but luminous materials with three emission characteristics have been largely undeveloped. Here, we report a novel zero-dimensional (0D) organic-inorganic hybrid ((C2H5)4N)2ZrCl6 perovskite with multiple emissions. The zirconium-based perovskite exhibits a red emission around 620 nm, a green emission at 527 nm, and a blue emission around 500 nm. The red and green emissions come from self-trapped excitons (STEs) and the d-d transitions of Zr(iv), respectively, which are caused by distortion of the [ZrCl6]2- octahedra. The blue emission is caused by thermally activated delayed fluorescence (TADF), which is similar to that of Cs2ZrCl6. The absolute photoluminescence quantum yield (PLQY) of the red and blue double emission is up to 83% and the PLQY of the green emission is 27%. With different combinations of ((C2H5)4N)2ZrCl6 samples, we achieve a variety of applications, including a two-color luminescent anti-counterfeiting device, a white light-emitting diode (WLED) with a color rendering index (CRI) of 95 and information encryption with different excitations. We also synthesize other hybrid zirconium perovskites with tri-luminescence through a similar method. Our work provides a potential set of excitation-dependent luminescent materials and is expected to expand the basic research and practical applications of multi-luminescence materials.

Luminescence Enhancement of CsMnBr3 Nanocrystals through Heterometallic Doping.

The absorption and photoluminescence (PL) of CsMnBr3 with Mn(II) in octahedral crystal fields are extremely weak due to a d-d forbidden transition. Herein, we introduce a facile and general synthetic procedure that can prepare undoped and heterometallic doped CsMnBr3 NCs at room temperature. Importantly, both PL and absorption of CsMnBr3 NCs were significantly improved after doping a small amount of Pb2+ (4.9%). The absolute photoluminescence quantum yield (PL QY) of Pb-doped CsMnBr3 NCs is up to 41.5%, 11-fold higher than undoped CsMnBr3 NCs (3.7%). The PL enhancement is attributed to the synergistic effects between [MnBr6]4- units and [PbBr6]4- units. Furthermore, we verified the similar synergistic effects between [MnBr6]4- units and [SbBr6]4- units in Sb-doped CsMnBr3 NCs. Our results highlight the potential of tailoring luminescence properties of manganese halides through heterometallic doping.

Ultra-small α-CsPbI3 perovskite quantum dots with stable, bright and pure red emission for Rec. 2020 display backlights.

The synthesis of α-CsPbI3 perovskite quantum dots (QDs) with pure red emission around 630 nm is in high demand for display backlight application. However, the phase transition of α-CsPbI3 to yellow non-emitting δ-CsPbI3 has been proven to be a great challenge for the classic colloidal synthesis route for perovskite QDs in octadecene (ODE). Herein, we report a novel colloidal synthesis route by replacing ODE with lauryl methacrylate (LMA) as the reaction solvent to improve the solubility of precursors, resulting in small sized α-CsPbI3 QDs with a diameter of only 4.2 nm, which are the smallest red PQDs reported so far. The corresponding CsPbI3 QD films exhibit a tunable photoluminescence (PL) emission peak in the bright pure red region of 627 to 638 nm. The CsPbI3 QD polymer composite films with PL emission at 630 nm exhibit a superior photoluminescence quantum yield (PLQY) and photostability to mixed halide CsPbBrI2 films under intense illumination. Perovskite light emitting diodes (LED) with the color gamut reaching 96% of the Rec. 2020 standard are achieved using these films. This study provides a high-performance pure red fluorescent material with a robust, low-cost, and reproducible colloidal chemistry that will pave the way for the adoption of perovskite QDs in display backlight application.

Solid-state synthesis of cesium manganese halide nanocrystals in glass with bright and broad red emission for white LEDs.

Recently, lead halide perovskite nanocrystals (NCs) have attracted extensive attention due to their unique optical properties. However, the toxicity of lead and the instability to moisture obstruct their further commercial development. Herein, a series of lead-free CsMnX3 (X = Cl, Br, and I) NCs embedded in glasses were synthesized by a high temperature solid-state chemistry method. These NCs embedded in glass can remain stable after soaking in water for 90 days. It is found that increasing the amount of cesium carbonate in the synthesis process can not only prevent the oxidation of Mn2+ to Mn3+ and promote the transparency of glass in the 450-700 nm region, but also significantly increase its photoluminescence quantum yield (PLQY) from 2.9% to 65.1%, which is the highest reported value of the red CsMnX3 NCs so far. Using CsMnBr3 NCs with a red emission peak at 649 nm and full-width-at-half-maximum (FWHM) of 130 nm as the red light source, a white light-emitting diode (LED) device with International Commission on illumination (CIE) coordinates of (0.33, 0.36) and a color rendering index (CRI) of 94 was obtained. These findings, together with future research, are likely to yield stable and bright lead-free NCs for the next generation of solid-state lighting.

The assessment of Ki-67 for prognosis of gastroenteropancreatic neuroendocrine neoplasm patients: a systematic review and meta-analysis.

Background: Neuroendocrine neoplasm (NEN) is a group of rare tumors. Among which, gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is the most common group. The World Health Organization (WHO) classified these tumors into three different grades (G1, G2, and G3) based on Ki-67 and mitotic rate, and updated the classification in 2019. Several previous studies proved that Ki-67 was related to tumor prognosis, but others still reported that Ki-67 had no predictive value for tumor prognosis. There are different conclusions between studies regarding the correlation between Ki-67 and tumor prognosis, and there is a lack of studies about this correlation of GEP-NENs. Further analysis is still needed to evaluate the prognostic value of Ki-67 in GEP-NENs, to provide reference for clinical decisions. Methods: A total of 303 studies were retrieved that included Ki-67, GEP-NENs, prognosis, survival, and other subject terms and keywords. We excluded studies that did not show complete Ki-67 index, number of patients and 5-year survival data available for meta-analysis, non-cohort studies, articles published before 2000 or not published in English. Fifteen studies were finally included to assess the value of Ki-67 in the prognosis of patients with GEP-NENs using a random-effects model. Results: The cumulative 5-year survival rate for GEP-NEN G1 (Ki-67 ≤2%), G2 (Ki-67 2-20%) and G3 (Ki-67 >20%) was 86%, 65%, 25% respectively. The 5-year survival rate of GEP-NEN G1 (Ki-67 <3%, first revised in WHO classification 2017, redefined WHO classification 2019) and G1 (Ki-67 ≤2%, WHO classification 2010) was 97% and 84% respectively. Conclusions: The overall prognosis of GEP-NENs patients showed a decreasing trend with the increase of Ki-67, which confirmed the significance of Ki-67 index as a prognostic marker for the prognosis of GEP-NENs. Increasing the cut-off value of Ki-67 index for G1 grade from ≤2% to <3% according to WHO classification 2019 did not significantly decrease the 5-year survival rate.

Loss of function of GATA3 regulates FRA1 and c-FOS to activate EMT and promote mammary tumorigenesis and metastasis.

Basal-like breast cancers (BLBCs) are among the most aggressive cancers, partly due to their enrichment of cancer stem cells (CSCs). Breast CSCs can be generated from luminal-type cancer cells via epithelial-mesenchymal transition (EMT). GATA3 maintains luminal cell fate, and its expression is lost or reduced in BLBCs. However, deletion of Gata3 in mice or cells results in early lethality or proliferative defects. It is unknown how loss-of-function of GATA3 regulates EMT and CSCs in breast cancer. We report here that haploid loss of Gata3 in mice lacking p18Ink4c, a cell cycle inhibitor, up-regulates Fra1, an AP-1 family protein that promotes mesenchymal traits, and downregulates c-Fos, another AP-1 family protein that maintains epithelial fate, leading to activation of EMT and promotion of mammary tumor initiation and metastasis. Depletion of Gata3 in luminal tumor cells similarly regulates Fra1 and c-Fos in activation of EMT. GATA3 binds to FOSL1 (encoding FRA1) and FOS (encoding c-FOS) loci to repress FOSL1 and activate FOS transcription. Deletion of Fra1 or reconstitution of Gata3, but not reconstitution of c-Fos, in Gata3 deficient tumor cells inhibits EMT, preventing tumorigenesis and/or metastasis. In human breast cancers, GATA3 expression is negatively correlated with FRA1 and positively correlated with c-FOS. Low GATA3 and FOS, but high FOSL1, are characteristics of BLBCs. Together, these data provide the first genetic evidence indicating that loss of function of GATA3 in mammary tumor cells activates FOSL1 to promote mesenchymal traits and CSC function, while concurrently repressing FOS to lose epithelial features. We demonstrate that FRA1 is required for the activation of EMT in GATA3 deficient tumorigenesis and metastasis.

Promoting the doping efficiency and photoluminescence quantum yield of Mn-doped perovskite nanocrystals via two-step hot-injection.

Manganese-doped perovskite nanocrystals (NCs) have been synthesized by a novel two-step hot-injection strategy with an unprecedented Mn doping efficiency of 48.5%, bright orange emission under ultraviolet light and X-ray excitation and a photoluminescence quantum yield of 84.4%, making them excellent luminescent materials.

Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFßR2 signaling pathway.

BRCA1 deficient breast cancers are aggressive and chemoresistant due, in part, to their enrichment of cancer stem cells that can be generated from carcinoma cells by an epithelial-mesenchymal transition (EMT). We previously discovered that BRCA1 deficiency activates EMT in mammary tumorigenesis. How BRCA1 controls EMT and how to effectively target BRCA1-deficient cancers remain elusive. We analyzed murine and human tumors and identified a role for Tgfßr2 in governing the molecular aspects of EMT that occur with Brca1 loss. We utilized CRISPR to delete Tgfßr2 and specific inhibitors to block Tgfßr2 activity and followed up with the molecular analysis of assays for tumor growth and metastasis. We discovered that heterozygous germline deletion, or epithelia-specific deletion of Brca1 in mice, activates Tgfßr2 signaling pathways in mammary tumors. BRCA1 depletion promotes TGFß-mediated EMT activation in cancer cells. BRCA1 binds to the TGFßR2 locus to repress its transcription. Targeted deletion or pharmaceutical inhibition of Tgfßr2 in Brca1-deficient tumor cells reduces EMT and suppresses tumorigenesis and metastasis. BRCA1 and TGFßR2 expression levels are inversely related in human breast cancers. This study reveals for the first time that a targetable TGFßR signaling pathway is directly activated by BRCA1-deficiency in the induction of EMT in breast cancer progression.

Synthesis of two-dimensional phenylethylamine tin-lead halide perovskites with bandgap bending behavior.

Recently, two-dimensional (2D) metal halide perovskite materials with wide application in perovskite-based solar cells have attracted significant attention. Among them, 2D mixed lead-tin perovskites have not been systematically explored. Herein, we synthesize a 2D phenethylammonium (PEA) tin-lead bromide perovskite, PEA2Sn x Pb1-x Br4, via a simple solution-phase approach without toxic reagents and high temperatures. By tuning the ratio of Sn and Pb, the UV-vis absorption spectra showed unique bandgap bending behaviors. DFT calculations indicate the key effects of spin-orbital coupling (SOC) without the interference of lattice distortion. Moreover, we provided the standard equation with a correction term to introduce the influence of SOC. These results not only provide a step forward towards the bandgap engineering of perovskites, but also help to expand the application of 2D perovskite materials.

GATA3 functions downstream of BRCA1 to suppress EMT in breast cancer.

Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18INK4C , a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18INK4C , to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.

Recombinant Dual-target MDM2/MDMX Inhibitor Reverses Doxorubicin Resistance through Activation of the TAB1/TAK1/p38 MAPK Pathway in Wild-type p53 Multidrug-resistant Breast Cancer Cells.

Chemotherapy resistance represents a major obstacle for the treatment of patients with breast cancer (BC) and greatly restricts the therapeutic effect of the first-line chemotherapeutic agent doxorubicin (DOX). The present study aimed to investigate the feasibility of the recombinant dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor in reversing the DOX resistance of BC. Both DOX-resistant human breast carcinoma cell lines exhibited a multidrug resistance (MDR) phenotype. The ability of the dual-target MDM2/MDMX inhibitor in reversing doxorubicin resistance was subsequently verified, (9.15 and 13.92 - fold reversal indexes) respectively. We observed that the MDM2/MDMX inhibitor in combination with DOX could suppress proliferation, promote cell cycle arrest and induce apoptosis. In addition, it was capable of reducing rhodamine123 efflux in DOX-resistance BC cell lines and further played a key role in BC nude mice model. The groups that were treated with the combination of the drugs had decreased P-glycoprotein/multidrug resistance-associated protein/cdc 2/Bcl-2 expression and increased CyclinB1/Bax expression. These effects were caused due to activation of the transforming growth factor ß-activated kinase 1 (TAK1)-binding protein 1 (TAB1)/TAK1/p38 mitogen-activated protein kinase (MAPK) signaling pathway, as shown by small interfering RNA (siRNA) silencing and immumohistochemical staining of BC tissue sections. Furthermore, high MDM2/MDMX expression was positively associated with weak TAB1 expression in BC patients. Therefore, the recombinant dual-target MDM2/MDMX inhibitor could reverse doxorubicin resistance via the activation of the TAB1/TAK1/p38 MAPK pathway in wild-type p53 multidrug-resistant BC.