The ROS/SIRT1/STAR axis as a target for melatonin ameliorating atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells.

The granulosa cells (GCs) of birds are essential for the reproduction and maintenance of populations in nature. Atrazine (ATR) is a potent endocrine disruptor that can interfere with reproductive function in females and Diaminochlorotriazine (DACT) is the primary metabolite of ATR in the organism. Melatonin (MT) is an endogenous hormone with antioxidant properties that plays a crucial role in development of animal germ cells. However, how ATR causes mitochondrial dysfunction, abnormal secretion of steroid hormones, and whether MT prevents ATR-induced female reproductive toxicity remains unclear. Thus, the purpose of this study is to investigate the protective effect of MT against ATR-induced female reproduction. In the present study, the GCs of quail were divided into 6 groups, as follows: C (Serum-free medium), MT (10 µM MT), A250 (250 µM ATR), MA250 (10 µM MT+250 µM ATR), D200 (200 µM DACT) and MD200 (10 µM MT+200 µM DACT), and were cultured for 24 h. The results revealed that ATR prevented GCs proliferation and decreased cell differentiation. ATR caused oxidative damage and mitochondrial dysfunction, leading to disruption of steroid synthesis, which posed a severe risk to GC's function. However, MT supplements reversed these changes. Mechanistically, our study exhibited that the ROS/SIRT1/STAR axis as a target for MT to ameliorate ATR-induced mitochondrial dysfunction and steroid disorders in GCs, which provides new insights into the role of MT in ATR-induced reproductive capacity and species conservation in birds.

Hsa_circ_0001402 alleviates vascular neointimal hyperplasia through a miR-183-5p-dependent regulation of vascular smooth muscle cell proliferation, migration, and autophagy.

INTRODUCTION: Vascular neointimal hyperplasia, a pathological process observed in cardiovascular diseases such as atherosclerosis and pulmonary hypertension, involves the abundant presence of vascular smooth muscle cells (VSMCs). The proliferation, migration, and autophagy of VSMCs are associated with the development of neointimal lesions. Circular RNAs (circRNAs) play critical roles in regulating VSMC proliferation and migration, thereby participating in neointimal hyperplasia. However, the regulatory roles of circRNAs in VSMC autophagy remain unclear. OBJECTIVES: We aimed to identify circRNAs that are involved in VSMC autophagy-mediated neointimal hyperplasia, as well as elucidate the underlying mechanisms. METHODS: Dual-luciferase reporter gene assay was performed to validate two competing endogenous RNA axes, hsa_circ_0001402/miR-183-5p/FKBP prolyl isomerase like (FKBPL) and hsa_circ_0001402/miR-183-5p/beclin 1 (BECN1). Cell proliferation and migration analyses were employed to investigate the effects of hsa_circ_0001402, miR-183-5p, or FKBPL on VSMC proliferation and migration. Cell autophagy analysis was conducted to reveal the role of hsa_circ_0001402 or miR-183-5p on VSMC autophagy. The role of hsa_circ_0001402 or miR-183-5p on neointimal hyperplasia was evaluated using a mouse model of common carotid artery ligation. RESULTS: Hsa_circ_0001402 acted as a sponge for miR-183-5p, leading to the suppression of miR-183-5p expression. Through direct interaction with the coding sequence (CDS) of FKBPL, miR-183-5p promoted VSMC proliferation and migration by decreasing FKBPL levels. Besides, miR-183-5p reduced BECN1 levels by targeting the 3'-untranslated region (UTR) of BECN1, thus inhibiting VSMC autophagy. By acting as a miR-183-5p sponge, overexpression of hsa_circ_0001402 increased FKBPL levels to inhibit VSMC proliferation and migration, while simultaneously elevating BECN1 levels to activate VSMC autophagy, thereby alleviating neointimal hyperplasia. CONCLUSION: Hsa_circ_0001402, acting as a miR-183-5p sponge, increases FKBPL levels to inhibit VSMC proliferation and migration, while enhancing BECN1 levels to activate VSMC autophagy, thus alleviating neointimal hyperplasia. The hsa_circ_0001402/miR-183-5p/FKBPL axis and hsa_circ_0001402/miR-183-5p/BECN1 axis may offer potential therapeutic targets for neointimal hyperplasia.

Lipopolysaccharide and lipoteichoic acid regulate the PI3K/AKT pathway through osteopontin/integrin ß3 to promote malignant progression of non-small cell lung cancer.

Background: Lung cancer (LC) is a malignancy with one of the highest mortality rates. Respiratory microbiota is considered to play a key role in the development of LC, but the molecular mechanisms are rarely studied. Methods: We used lipopolysaccharide (LPS) and lipoteichoic acid (LTA) to study human lung cancer cell lines PC9 and H1299. The gene expression of CXC chemokine ligand (CXCL)1/6, interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The Cell-Counting Kit 8 (CCK-8) was used to analyze cell proliferation. Transwell assays were performed to analyze cell migration ability. Flow cytometry was used to observe cell apoptosis. Western blot and qRT-PCR were used to analyze the expression of secreted phosphoprotein 1 (SPP1), toll-like receptor (TLR)-2/4, and NLR family pyrin domain containing 3 (NLRP3) to determine the mechanism of LPS + LTA. We evaluated the effect of LPS + LTA on cisplatin sensibility by analyzing cell proliferation, apoptosis, and caspase-3/9 expression levels. We observed the proliferation activity, apoptosis, and migration ability of cells in which SPP1 had been transfected small interfering (si) negative control (NC) and integrin ß3 siRNA. Then the mRNA expression level and protein expression of PI3K, AKT, and ERK were analyzed. Finally, the nude mouse tumor transplantation model was conducted to verify. Results: We studied that in two cell lines, the expression level of inflammatory factors in LPS+LTA group was significantly higher than that in single treatment group (P<0.001). We explored LPS + LTA combined treatment group significantly increased the expression of NLRP3 and genes and proteins. LPS + LTA + Cisplatin group could significantly reduce the inhibitory effect of LPS on cell proliferation (P<0.001), reduce the apoptosis rate (P<0.001) and significantly reduce the expression levels of caspase-3/9 (P<0.001) compared with Cisplatin group. Finally, we verified that LPS and LTA could increase osteopontin (OPN)/integrin ß3 expression and activate the PI3K/AKT pathway to promote malignant progression of LC in vitro studies. Conclusions: This study provides a theoretical basis for further exploration of the influence of lung microbiota on NSCLC and the optimization of LC treatment in the future.

IL-6/STAT3/Foxo1 axis as a target of lycopene ameliorates the atrazine-induced thymic mitophagy and pyroptosis cross-talk.

The intensive adoption of atrazine (ATZ) is a source of a persistently widespread pollutant in daily life. However, ATZ is still used as an essential herbicide in numerous countries because its toxic effect is not addressed as a public health concern. This study found that ATZ exposure caused mitophagy and pyroptosis crosstalk in the thymus. And it could destroy the thymus architecture, inducing immunodeficiency. Lycopene (LYC), a natural bioactive component, is applied to reduce the risk of chronic diseases caused by environmental factors. This work also investigated the health benefits of LYC in the ATZ-induced toxic effect on the thymus. LYC could ameliorate the ATZ-induced mitophagy and pyroptosis. LYC modulated the IL-6/STAT3/Foxo1 axis, improving the level of CD45 in the thymus. This work sheds light on the toxic effect of ATZ on the thymus, and it will provide evidence for ATZ health risks. Additionally, the finding also underscores a novel target of LYC in maintaining thymic homeostasis in ATZ exposure.

Serum albumin guided plasmonic nanoassemblies with opposite chiralities.

Chiral assemblies by combining natural biomolecules with plasmonic nanostructures hold great promise for plasmonic enhanced sensing, imaging, and catalytic applications. Herein, we demonstrate that human serum albumin (HSA) and porcine serum albumin (PSA) can guide the chiral assembly of gold nanorods (GNRs) with left-handed chiroptical responses opposite to those by a series of other homologous animal serum albumins (SAs) due to the difference of their surface charge distributions. Under physiological pH conditions, the assembly of HSA or PSA with GNRs yielded left-handed twisted aggregates, while bovine serum albumin (BSA), sheep serum albumin, and equine serum albumin behaved on the contrary. The driving force for the chiral assembly is mainly attributed to electrostatic interaction. The opposite chiroptical signals acquired are correlated with the chiral surface charge distributions of the tertiary structures of SAs. Moreover, the chirality of the assembly induced by both HSA and BSA can be enhanced or reversed by adjusting the pH values. This work provides new insights into the modulation of protein-induced chiral assemblies and promotes their applications.

[Study on liver diseases with zebrafish as an important tool].

With the increasing incidence of hepatobiliary diseases, it is particularly important to understand the role of molecular, cellular and physiological factors in the clinical diagnosis and treatment with traditional Chinese medicine(TCM) in the development of liver disease. Appropriate animal models can help us identify the possible mechanisms of relevant diseases. Danio rerio(zebrafish) model was traditionally used to study embryonic development, and has been gradually used in screening and evaluation of liver diseases and relevant drug in recent years. Zebrafish embryos develop rapidly and the digestive organs of 5-day-old juvenile fish are all mature. At this stage, they may develop hepatobiliary diseases induced by developmental defects or compounds. Zebrafish liver is similar to human liver in cell composition, function, signal transduction, response to injury and cell process mediating liver disease. Furthermore, due to the high conservation of genes and proteins between humans and zebrafish, zebrafish becomes an alternative system for studying basic mechanisms of liver disease. Therefore, genetic screening could be performed to identify new genes involving specific disease processes, and chemical screening could be made for drugs in specific processes. This paper briefly introduced the experimental properties of zebrafish as model system, emphasized the study progress of zebrafish models for pathological mechanism of liver diseases, especially fatty liver, and drug screening and evaluation, so as to provide ideas and techniques for the future liver toxicity assessment of TCM.

Elaborate Design of d8-d10 Heteronuclear Phosphors for Ultrahigh-Efficiency Solution-Processed Organic Light-Emitting Diodes.

Highly soluble d8-d10 heteronuclear phosphors afford an alternative approach to achieve high-efficiency organic light-emitting diodes (OLEDs) through a solution process. In this work, four highly phosphorescent d8-d10 heteronuclear complexes with significant Pt-Au interactions were prepared. By judicious selection of sterically hindered and π-conjugated substituents in triphosphine ligands, the phosphorescence is dramatically promoted through effectively prohibiting nonradiative thermal relaxation with an efficiency of 0.94-0.99 in doping films. Exploiting highly emissive Pt-Au complexes as phosphorescent dopants, ultrahigh-efficiency solution-processed OLEDs were attained. The peak current efficiency, power efficiency, and external quantum efficiency are 96.2 cd A-1, 65.0 lm W-1, and 26.4% for the green-emitting PtAu2 phosphor and 68.6 cd A-1, 42.5 lm W-1, and 25.1% for the orange-emitting Pt2Au phosphor, which represent the state-of-art for solution-processed OLEDs based on non-iridium phosphors.

Objective visual quality one year after toric IOL implantation for correction of moderate and high corneal astigmatism.

AIM: To compare the objective visual quality after implantation of a toric intraocular lens (IOL) in order to correct moderate or high corneal astigmatism at the one year postoperative follow-up. METHODS: From December 2017 to June 2018, 66 patients (90 eyes) with simple age-related cataract with regular corneal astigmatism greater than 1.5 D were enrolled in this prospective self-control study. The patients were implanted with Proming® toric IOL (model: AT3BH-AT6BH). The subjects were divided into moderate astigmatism group (46 eyes, 1.5-2.5 D) and high astigmatism group (44 eyes, >2.5 D). The uncorrected distance visual acuity, residual astigmatism and axial position of IOL were observed before operation, 3, 6mo and 1y after operation. Modulation transfer function cutoff (MTF cutoff), Strehl ratio (SR), object scatter index (OSI) were observed by OQAS II to evaluate the objective visual quality of patients. RESULTS: There was no significant difference in UCVA, residual astigmatism, axial deviation, MTF cutoff, SR and OSI between moderate and high astigmatism group (all P>0.05). After 3mo, UCVA, MTF cutoff and SR were significantly increased (all P<0.05), residual astigmatism and OSI were significantly decreased (all P<0.05). After 3mo, all the indexes remained stable. CONCLUSION: Proming toric IOL can effectively treat age-related cataract patients with moderate-to-high regular corneal astigmatism, correcting corneal astigmatism, improving UCVA, ensuring long-term stability in the capsule, and providing patients with better visual quality.

Integrated strategy of LC-MS and network pharmacology for predicting active constituents and pharmacological mechanisms of Ranunculus japonicus Thunb. for treating rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ranunculus japonicus Thunb. (short for R. japonicus) is a topically applied herb with the activities of removing jaundice, nebula and edema, preventing malaria, stopping asthma, promoting diuresis and relieving pain. It was firstly recorded in Zhouhou Beiji Fang and has been used for the treatment of malaria, ulcers, carbuncle, jaundice, migraine, stomachache, toothache and arthritis for over 1800 years. AIM OF THE STUDY: This study aimed to uncover the potentially effective components of R. japonicus and the pharmacological mechanisms against rheumatoid arthritis (RA) by combing LC-MS and network pharmacology. MATERIALS AND METHODS: Firstly, the chemical constituents of R. japonicus were qualitatively identified by UPLC-ESI-LTQ-Orbitrap MS. Then we performed target prediction by PharmMapper, protein-protein interaction (PPI) analysis via String, GO and KEGG pathway enrichment analysis by DAVID and constructed the compound-target-pathway network using Cytoscape. Thirdly, crucial compounds in the network were quantitatively analyzed to achieve quality control of R. japonicus. Finally, the pharmacological activities of R. japonicus and two potentially bioactive ingredients were validated in RA-FLSs (Rheumatoid Arthritis Fibroblast-like Synoviocytes) in vitro. RESULTS: Overall fifty-four ingredients of R. japonicus were identified and forty-five components were firstly discovered in R. japonicus. Among them, twenty-seven validated compounds were predicted to act on twenty-five RA-related targets and they might exhibit therapeutic effects against RA via positive regulation of cell migration, etc. Nine potentially bioactive components of R. japonicus which played important roles in the compound-target-pathway network were simultaneously quantified by an optimized UPLC-ESI-Triple Quad method. In vitro, compared to control group, R. japonicus extract, berberine and yangonin significantly inhibited the migration capacity of RA-FLSs after 24 h treatment. CONCLUSION: This study clarified that R. japonicus and the bioactive ingredients berberine and yangonin might exert therapeutic actions for RA via suppressing the aggressive phenotypes of RA-FLSs through combined LC-MS technology and network pharmacology tools for the first time. The present research provided deeper understanding into the chemical profiling, pharmacological activities and quality control of R. japonicus and offered reference for further scientific research and clinical use of R. japonicus in treating RA.

Integrated UPLC-MS and Network Pharmacology Approach to Explore the Active Components and the Potential Mechanism of Yiqi Huoxue Decoction for Treating Nephrotic Syndrome.

Background: Yiqi Huoxue Decoction (YQHXD) is a traditional Chinese medicine that promotes blood circulation, removes blood stasis, facilitates diuresis, and alleviates edema. It is composed of 10 herbal medicines and has extensive application in treating nephrotic syndrome (NS). However, the active components and the potential mechanism of YQHXD for treating NS remain unclear. Methods: We set up a sensitive and rapid method based on Ultra-High Performance Liquid Chromatograph-Mass (UPLC-MS) to identify the compounds in YQHXD and constituents absorbed into the blood. Disease genes were collected through GeneCards, DisGeNET, and OMIM database. Genes of compounds absorbed into blood were predicted by the TCMSP database. We constructed Disease-Drug-Ingredient-Gene (DDIG) network using Cytoscape, established a Protein-protein interaction (PPI) network using String, Gene biological process (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using DAVID. Cellular experiments were performed to validate the results of network pharmacology. Result: A total of 233 compounds in YQHXD and 50 constituents absorbed into the blood of rats were identified. The 36 core targets in the PPI network were clustered in the phosphatidylinositol 3 kinase-RAC serine/threonine-protein kinase (PI3K-AKT) and nuclear factor kappa-B (NF-κB) signaling pathways. Luteolin, Wogonin, Formononetin, and Calycosin were top-ranking components as potentially active compounds. Conclusion: The results of our studies show that YQHXD is able to enhance renal function, alleviate podocyte injury, and improve adriamycin nephrotic syndrome.

Large-area, low-cost near-infrared meta-surface reflector based on a pixelated two-dimensional silicon disk array.

All-dielectric meta-surfaces composed of dielectric meta-atoms with electric and magnetic multipole resonances provide a low loss alternative to plasmonic meta-surfaces in some optical research fields such as meta-lens and meta-surface holography. We utilize the digital holography lithography technique to obtain the large area meta-surface perfect reflector made of high refractive index and low loss silicon discs arrays, with the capability to delicately control the optical response in the near infrared spectrum. Three types of meta-surface reflectors (discs, truncated cones and diamond-shaped discs) were fabricated, which correspondingly exhibited nearly 1 peak reflectance and greater than 97% average reflectance in their respective perfect reflectance spectral regions. Digital holography lithography only takes 4 min to fabricate millions of photoresist disks over an area of 100 mm2, which is high processing efficiency and low cost. The fabrication strategy opens a new avenue for the production of large-area meta-surfaces in the optical field, especially in the mass production of optical communication devices, semiconductor lasers, etc.

From homonuclear to heteronuclear: a viable strategy to promote and modulate phosphorescence.

Numerous mononuclear platinum(ii) complexes are non-emissive or weakly emissive under ambient conditions, but the corresponding Pt-M (M = Cu(i), Ag(i), Au(i), etc.) heteronuclear assemblies could become intensely luminescent because of the inhibition of non-radiative relaxation and the promotion of intersystem crossing from singlet to triplet state through Pt-M intermetallic interactions. To this end, the fabrication of specifically structured Pt-M complexes by the use of slightly luminescent homonuclear Pt(ii) precursors provides a promising approach to switching on phosphorescence as well as modulating emission energy and colour. This feature article is aimed at providing some typical examples for attaining highly phosphorescent Pt-M heteronuclear complexes using homonuclear Pt(ii) precursors, focusing on the assembly strategy, the correlation of emissive properties to the structures, and the application of phosphorescence in sensing and light-emitting devices.

The ER-α36/EGFR signaling loop promotes growth of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the common primary liver cancer and the third leading cause of cancer related mortality worldwide. It is generally thought that the estrogen-signaling pathway is not related to the development and progression of human HCC. However, accumulating evidences indicate the existence of a rapid estrogen signaling in HCC cells that is able to promote cell growth. However, the receptor that mediates the rapid estrogen signaling in HCC cells has not been established. Previously, our laboratory identified a variant of ER-α, ER-α36, and found that ER-α36 mediates the rapid estrogen signaling such as the activation of the MAPK/ERK signaling in breast carcinoma cells. Our current experiments studied the role of the rapid estrogen signaling mediated by ER-α36 in growth of HCC HepG2 and PLC/PRF/5 cells that highly express ER-α36 and found these cells were strongly responsive to the rapid estrogen signaling. Knockdown of ER-α36 expression in these HCC cells using the shRNA method attenuated their responsiveness to estrogen and destabilized EGFR protein. ER-α36 mediated estrogen-induced phosphorylation of Src and the MAPK/ERK as well as cyclin D1 expression. In addition, there existed an ER-α36/EGFR positive regulatory loop in HCC cells that was important for the maintenance and positive regulation of HCC tumorsphere cells. Our results thus indicated that the rapid estrogen receptor is mediated by ER-α36 in HCC cells through the EGFR/Src/ERK signaling pathway and suggested that the ER-α36/EGFR signaling loop is a potential target to develop novel therapeutic approaches for HCC treatment.

Advance in quality assessment of Chinese materia medica using microscopic and morphological methods.

Quality evaluation plays a vital role in ensuring safety and effectiveness of Chinese materia medica (CMM). Microscopic and morphological technologies can be used to distinguish CMM's characteristics, such as shape, size, texture, section, and smell, for authenticity and quality control of CMM. The microscopic and morphological applications of novel micro-technology, colorimeter, and texture analyzer for CMM identification are summarized and the future prospect is discussed in this paper. Various styles and complex sources of CMM are systemically reviewed, including cormophyte medicinal materials, fruit and seeds, pollen grain, and spore materials.

Chiral Plasmonic Nanochains via the Self-Assembly of Gold Nanorods and Helical Glutathione Oligomers Facilitated by Cetyltrimethylammonium Bromide Micelles.

Gold nanorods are excellent anisotropic building blocks for plasmonic chiral nanostructures. The near-infrared plasmonic band of nanorods makes them highly desirable for biomedical applications such as chiral bioimaging and sensing, in which a strong circular dichroism (CD) signal is required. Chiral assemblies of gold nanorods induced by self-associating peptides are especially attractive for this purpose as they exhibit plasmonic-enhanced chiroptical activity. Here, we showed that the presence of cetyltrimethylammonium bromide (CTAB) micelles in a gold nanorod solution promoted the self-association of l-/d-glutathione (GSH) and significantly enhanced the chirality of the resulting plasmonic nanochains. Chiroptical signals for the ensemble in the presence of CTAB micelles were 20 times greater than those obtained below the critical micelle concentration of CTAB. The strong optical activity was attributed to the formation of helical GSH oligomers in the hydrophobic core of the CTAB micelles. The helical GSH oligomers led the nanorods to assemble in a chiral, end-to-end crossed fashion. The CD signal intensities were also proportional to the fraction of nanorods in the nanochains. In addition, finite-difference time-domain simulations agreed well with the experimental extinction and CD spectra. Our work demonstrated a substantial effect from the CTAB micelles on gold nanoparticle assemblies induced by biomolecules and showed the importance of size matching between the inorganic nanobuilding blocks and the chiral molecular templates (i.e., the GSH oligomers in the present case) in order to attain strong chiroptical activities.

Potential health risk for residents around a typical e-waste recycling zone via inhalation of size-fractionated particle-bound heavy metals.

Health risk of residents dwelling around e-waste recycling zones has been a global concern, but has not been adequately examined. The present study was intended to evaluate the potential health risk of residents through inhalation exposure to size-fractionated particle-bound heavy metals in a typical e-waste recycling zone, South China. Anthropogenic metals (Zn, Se, Pb, Sb, As, and Cd) were predominantly enriched in fine particles (Dp<1.8µm), whereas the crustal elements (Ti, Fe, and Co) tended to accumulate in coarse particles (Dp>1.8µm). Although the daily inhalation intakes of the target metals were significantly lower than those through food consumption and ingestion of house dust, the hazard quotients of total metals for adults (95% CI: 1.0-5.5) and children (95% CI: 3.0-17) were greater than 1. Moreover, the incremental lifetime cancer risks of five carcinogenic metals (Cr, Co, Ni, As, and Cd) for adults and children were 1.3×10(-3) (95% CI: 4.1×10(-4)-3.0×10(-3)) and 3.9×10(-3) (95% CI: 1.3×10(-3)-8.6×10(-3)), respectively, substantially higher than the acceptable cancer risk range of 10(-6)-10(-4). All these findings suggested that health risks were high for local residents dwelling around the e-waste recycling zone through inhalation exposure to particle-bound heavy metals, for both adults and children.

Roles of the ER-α36-EGFR/HER2 positive regulatory loops in tamoxifen resistance.

Tamoxifen provided a successful treatment for ER-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to tamoxifen therapy. Extensive researches were conducted to understand the molecular mechanisms involved in tamoxifen resistance, and have revealed that multiple signaling molecules and pathways such as EGFR and HER2 are involved in tamoxifen resistance. Currently, the mechanisms by which tamoxifen sensitive breast cancer cells acquire these signaling pathways and develop tamoxifen resistance have not been elucidated. The identification of ER-α36, a variant of ER-α, that is able to mediate agonist activity of tamoxifen provided great insights into the underlying mechanisms of tamoxifen resistance. In this review, we will discuss the biological function and the possible underlying mechanisms of ER-α36 in tamoxifen resistance and specifically illustrate a novel cross-talk mechanism; positive regulatory loops between the ER-α36 and EGFR/HER2 in tamoxifen resistance. The function and the underlying mechanisms of ER-α36 in tamoxifen resistance of the breast cancer stem/progenitor cells will also be discussed. Finally, we will postulate a novel approach to restore tamoxifen sensitivity in tamoxifen resistant breast cancer cells.

Downregulation of ER-α36 expression sensitizes HER2 overexpressing breast cancer cells to tamoxifen.

Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, HER2 overexpressing breast cancer cells respond poorly to tamoxifen therapy presumably by pass. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-α36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-α36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-α36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-α36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-α36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-α36-EGFR/HER2 loops.

Estrogen receptor alpha-36 (ER-α36): A new player in human breast cancer.

Prevailing wisdom is that estrogen receptor (ER)-α mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-α, ER-α36, and found that ER-α36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-α36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-α36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross-talk of ER-α36 with other ERs and growth factor receptors, and intracellular pathways of ER-α36-mediated rapid estrogen signaling. The potential function and underlying mechanism of ER-α in development of ER-positive breast cancer will also be discussed.

Disruption of the ER-α36-EGFR/HER2 positive regulatory loops restores tamoxifen sensitivity in tamoxifen resistance breast cancer cells.

Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, most breast tumors develop tamoxifen resistance and are eventually refractory to tamoxifen therapy. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-α36, a variant of ER-α, were resistant to tamoxifen and knockdown of ER-α36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-α36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-α36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-α36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-α36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-α36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-α36-EGFR/HER2 loops.