Androgen receptor and heat shock protein 27 co-regulate the malignant potential of molecular apocrine breast cancer

Abstract Background The most striking feature of molecular apocrine breast cancer (MABC) is the expression of androgen receptor (AR). We report here the mechanism of the AR in regulating the behavior of MABC. Methods The MABC cell line, MDA-MB-453, and the nonMABC cell line, MCF7, were used in this study. The effect of dihydrotestosterone (DHT) and heat shock protein 27 (HSP27) on cell proliferation was quantified using the cell counter kit-8 (CCK8) and clonogenic assays in vitro and by a xenograft tumor model in vivo. The expression of the AR and HSP27 was analyzed using western blot, qPCR, and immunofluorescence assays. Complexes of the AR and HSP27 were detected by co-immunoprecipitation (Co-IP). Results In MDA-MB-453 cells, DHT promoted cell proliferation and stimulated AR and HSP27 translocation from the cytoplasm to the nucleus, whereas, it inhibited MCF7 cell growth, and only the AR translocated into the nucleus. HSP27 knock-down decreased the proliferative ability of MDA-MB-453 cells, which could be rescued by DHT, while HSP27 and DHT had synergistic effects on MCF7 cells. HSP27 phosphorylation was a prerequisite for AR translocation into the nucleus, especially phosphorylation on serine 82. In addition, DHT stimulated the tumorigenic and metastatic capacities of MDA-MB-453 cells, while HSP27 knock-down decreased the rate of tumor formation and induced apoptosis in cells. Conclusions The results suggest that HSP27 assists the AR in regulating the malignant behavior of MABC, and these findings might be helpful in the treatment of MABC

AR–PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer

Abstract Background Androgen receptor (AR) is expressed in 60%~ 70% oestrogen receptor (ER)-negative breast cancer (BC) cases and promotes the growth of this cancer subtype. Expression of prostate-derived Ets factor (PDEF), a transcription factor, is highly restricted to epithelial cells in hormone-regulated tissues. MYC and its negative regulator MAD1 play an important role in BC progression. Previously, we found that PDEF expression is strongly correlated with AR expression. However, the relationship between AR and PDEF and the function of PDEF in ER-negative BC proliferation are unclear. Methods AR and PDEF expression in ER-negative BC tissues and cell lines was determined by performing immunohistochemistry or western blotting. Protein expression levels and location were analysed by performing western blotting, RT-qPCR and immunofluorescence staining. Co-immunoprecipitation and chromatin immunoprecipitation assays were performed to validate the regulation of AR–PDEF–MAD1–MYC axis. Moreover, the effect of AR and PDEF on BC progression was investigated both in vitro and in vivo. Results We found that PDEF was overexpressed in ER-negative BC tissues and cell lines and appeared to function as an oncogene. PDEF expression levels were strongly correlated with AR expression in ER-negative BC, and PDEF transcription was positively regulated by AR. PDEF upregulated MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative BC. Finally, we found that compared with the inhibition of AR expression alone, simultaneous inhibition of AR and PDEF expression further suppressed tumour proliferation both in vitro and in vivo. Conclusions Our data highlight the role of the AR–PDEF–MAD1–MYC axis in BC progression and suggest that PDEF can be used as a new clinical therapeutic target for treating ER-negative BC

Development of Specific Molecular and Phenotypic Marker-Based Haploid Inducers in Rice

Doubled haploid (DH) technology is an efficient strategy for producing completely homozygous lines for breeding programs. Mutations in the MATRILINEAL (MTL) phospholipase trigger intraspecific haploid induction in cereals. Although an in vivo haploid induction system based on OsMTL-edited plants has been established in rice (Oryza sativa), DH technology is still limited by other factors, such as haploid identification, which is one of the essential steps required for DH technology. In the study, we addressed this technical challenge by integrating specific molecular and phenotypic markers into rice haploid inducers. We first generated large fragment insertion or deletion mutations within the OsMTL gene and designed a pair of primers flanking the mutational sites to be used as the specific and universal molecular markers between wild-type and Osmtl plants. Next, we screened for hairy leaf as a single dominant trait and integrated it into specific molecular marker-based haploid inducers using the cross and self-cross method. When crossing cytoplasmic male sterile lines with these haploid inducers, we utilized the specific InDel marker and hairy leaf phenotypic marker to identify putative haploids (or double haploids). These putative haploids were further confirmed through ploidy and phenotypic analysis, demonstrating the high efficiency of haploid identification using these markers. The haploid induction rate (HIR) of the developed specific molecular and phenotypic marker-based haploid inducers ranged from 3.7% to 12.5%. We have achieved successful integration of distinct molecular and phenotypic markers into rice haploid inducers. Our advanced marker-based system has significantly enhanced the accuracy of haploid identification, thereby expediting the adoption of DH technology in rice breeding

The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta

molecule

An approach to (±)-Lingzhiol

(±)-Lingzhiol has been synthesized from commercially available 5,8-dimethoxytetralone in seven steps with an overall yield of 10.3% via an unprecedented acid-catalyzed semipinacol-type rearrangement. In addition, a novel strategy for the construction of the tetracyclic 5/5/6/6 core structure of lingzhiol has been developed via a tandem rearrangement/reduction/lactonization reaction

Enhancing cycle life of nickel-rich LiNi0.9Co0.05Mn0.05O2 via a highly fluorinated electrolyte additive - pentafluoropyridine

A highly fluorinated additive, pentafluoropyridine (PFP), is used here to enhance the interfacial stability of the Ni-rich LiNi0.9Co0.05Mn0.05O2 (NCM90) cathode at a cut-off voltage of 4.3 V vs. Li/Li+ at 30 °C. The capacity retention of the NCM90||Li cell is obviously improved from 72.3% to 80.3% after 200 cycles at 1C (1C = 180 mA g-1) when 0.2% PFP is introduced into the baseline electrolyte (1 mol L-1 LiPF6 in ethylene carbonate/diethyl carbonate). The improvement in electrochemical performance could be attributed to the formation of a compact and uniform cathode electrolyte interphase (CEI) layer enriched with F-containing polypyridine moieties and LiF species on the NCM90 particles. This CEI prevents side reactions between the electrode and electrolyte and hinders the corrosion of the cathode caused by HF attack. In addition, the formation of internal particle cracks is somewhat suppressed by the robust CEI, thus prohibiting the irreversible phase transformation and better maintaining the superior lithium-ion diffusion kinetics

A Unique Pattern of HCV Genotype Distribution on Hainan Island in China Revealed by Evolutionary Analysis

Background/Aims: Different genotypes of HCV may differ in both disease progression and response to antiviral therapies. Hainan Island has been inhabited by the “Li” aboriginal minority for centuries. We aimed to provide a better understanding of HCV infection on Hainan Island, so that the information would help improve strategies for HCV prevention and control on the island and in the wider country. Methods: Using RT-PCR and DNA sequencing, we determined HCV sequences from 100 patients living on Hainan Island. Results: Phylogenetic analysis classified these sequences into six subtypes: 6a (n=35), 1b (n=31), 3b (n=16), 2a (n=8), 3a (n=6), and 1a (n=4). By including reference sequences reported from elsewhere in China, phylogeographic trees were reconstructed to indicate their migration patterns. While the predominant 6a isolates were estimated to have origins in Guangdong and Guangxi provinces, the increase in 3b strains must have resulted from IDU network transmission from the southwest. A Bayesian Skyline Plot for subtype 1a, which is rare in China, showed a rapid population growth since 1998. Although slowed in rate around 2005, this growth continued to the present. Not found for any other HCV lineage. Conclusions: Overall, a delayed growth pattern may indicate the unique history of 1a dissemination in China and its recently increasing prevalence, despite measures taken to improve HCV prevention