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Targeting androgen receptor (AR) has shown great therapeutic potential in triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. Here, we aimed to identify promising targeted agents that synergize with enzalutamide, a second-generation AR inhibitor, in TNBC. By using a strategy for screening drug combinations based on the Sensitivity Index (SI), we found that MK-8776, a selective checkpoint kinase1 (CHK1) inhibitor, showed favorable synergism with enzalutamide in AR-positive TNBC. The combination of enzalutamide and MK-8776 was found to exert more significant anti-tumor effects in TNBC than the single application of enzalutamide or MK-8776, respectively. Furthermore, a nanoparticle-based on hyaluronic acid (HA)-modified hollow-manganese dioxide (HMnO2), named HMnE&M@H, was established to encapsulate and deliver enzalutamide and MK-8776. This HA-modified nanosystem managed targeted activation via pH/glutathione responsiveness. HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC.

Abstract. Background:. Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer associated with poor prognosis and limited treatment options. The androgen receptor (AR) has emerged as a potential therapeutic target for luminal androgen receptor (LAR) TNBC. However, multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits. This study aimed to investigate the role of AR in TNBC and its detailed mechanism. Methods:. Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4 (NECTIN4) expression in TNBC tissues. Then, in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta (ERβ) in TNBC. Chromatin immunoprecipitation sequencing (ChIP-seq), co-immunoprecipitation (co-IP), molecular docking method, and luciferase reporter assay were performed to identify key molecules that affect the function of AR. Results:. Based on the TNBC tissue array analysis, we revealed that ERβ and AR were positive in 21.92% (32/146) and 24.66% (36/146) of 146 TNBC samples, respectively, and about 13.70% (20/146) of TNBC patients were ERβ positive and AR positive. We further demonstrated the pro-tumoral effects of AR on TNBC cells, however, the oncogenic biology was significantly suppressed when ERβ transfection in LAR TNBC cell lines but not in AR-negative TNBC. Mechanistically, we identified that NECTIN4 promoter –42 bp to –28 bp was an AR response element, and that ERβ interacted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression. Conclusions:. This study suggests that ERβ functions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation. Therefore, our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

Abstract Breast cancer, a highly fatal disease due to its tendency to metastasize, is the most prevalent form of malignant tumors among women worldwide. Numerous studies indicate that breast cancer exhibits a unique predilection for metastasis to specific organs including the bone, liver, lung, and brain. However, different types of, The understanding of the heterogeneity of metastatic breast cancer has notably improved with the recent advances in high-throughput sequencing techniques. Focusing on the modification in the microenvironment of the metastatic organs and the crosstalk between tumor cells and in situ cells, noteworthy research points include the identification of two distinct modes of tumor growth in bone metastases, the influence of type II pneumocyte on lung metastases, the paradoxical role of Kupffer cells in liver metastases, and the breakthrough of the blood-brain barrier (BBB) breach in brain metastases. Overall, this review provides a comprehensive overview of the characteristics of breast cancer metastases, shedding light on the pivotal roles of immune and resident cells in the development of distinct metastatic foci. Graphical Abstract Video Abstract

Summary: It is imperative to explore biomarkers that are both precise and readily accessible in the comprehensive management of breast cancer. A multicenter cohort, including 512 breast cancer patients and 198 nonneoplastic individuals, was recruited to detect the level of tumor-derived extracellular vesicles using our method based on dual DNA tetrahedral nanostructures. The level of tumor-derived extracellular vesicles was significantly higher in newly diagnosed breast cancer patients than in nonneoplastic individuals at a cutoff value of 3.58 U/μL. For postoperative metastasis monitoring, the level of tumor-derived extracellular vesicles was significantly higher in breast cancer patients with metastasis than in those without metastasis at a cutoff value of 3.91 U/μL. Its efficacy of diagnosis and metastasis monitoring was superior to traditional tumor markers. Elevated level of tumor-derived extracellular vesicles served as a predictive biomarker for diagnosis and metastasis monitoring in breast cancer patients.

Abstract Background Intra-tumoral heterogeneity (ITH) is a distinguished hallmark of cancer, and cancer stem cells (CSCs) contribute to this malignant characteristic. Therefore, it is of great significance to investigate and even target the regulatory factors driving intra-tumoral stemness. c-Myc is a vital oncogene frequently overexpressed or amplified in various cancer types, including breast cancer. Our previous study indicated its potential association with breast cancer stem cell (BCSC) biomarkers. Methods In this research, we performed immunohistochemical (IHC) staining on sixty breast cancer surgical specimens for c-Myc, CD44, CD24, CD133 and ALDH1A1. Then, we analyzed transcriptomic atlas of 1533 patients with breast cancer from public database. Results IHC staining indicated the positive correlation between c-Myc and BCSC phenotype. Then, we used bioinformatic analysis to interrogate transcriptomics data of 1533 breast cancer specimens and identified an intriguing link among c-Myc, cancer stemness and copper-induced cell death (also known as “cuproptosis”). We screened out cuproptosis-related characteristics that predicts poor clinical outcomes and found that the pro-tumoral cuproptosis-based features were putatively enriched in MYC-targets and showed a significantly positive correlation with cancer stemness. Conclusion In addition to previous reports on its oncogenic roles, c-Myc showed significant correlation to stemness phenotype and copper-induced cell toxicity in breast cancer tissues. Moreover, transcriptomics data demonstrated that pro-tumoral cuproptosis biomarkers had putative positive association with cancer stemness. This research combined clinical samples with large-scale bioinformatic analysis, covered description and deduction, bridged classic oncogenic mechanisms to innovative opportunities, and inspired the development of copper-based nanomaterials in targeting highly heterogeneous tumors.

CRISPR, as an emerging gene editing technology, has been widely used in multiple fields due to its convenient operation, less cost, high efficiency and precision. This robust and effective device has revolutionized the development of biomedical research at an unexpected speed in recent years. The development of intelligent and precise CRISPR delivery strategies in a controllable and safe manner is the prerequisite for translational clinical medicine in gene therapy field. In this review, the therapeutic application of CRISPR delivery and the translational potential of gene editing was firstly discussed. Critical obstacles for the delivery of CRISPR system in vivo and shortcomings of CRISPR system itself were also analyzed. Given that intelligent nanoparticles have demonstrated great potential on the delivery of CRISPR system, here we mainly focused on stimuli-responsive nanocarriers. We also summarized various strategies for CIRSPR-Cas9 system delivered by intelligent nanocarriers which would respond to different endogenous and exogenous signal stimulus. Moreover, new genome editors mediated by nanotherapeutic vectors for gene therapy were also discussed. Finally, we discussed future prospects of genome editing for existing nanocarriers in clinical settings.

Abstract Cancer treatment by inducing tumor cell immunogenic cell death (ICD) is critical for tumor therapy. However, ICD activation by single pathway is often limited in practical application due to its low efficiency. In addition, the low pH and anoxic microenvironments in solid tumors greatly limit the effective activation of ICD. Herein, hollow manganese dioxide (H-MnO2) nanomaterials were selected to load both Mitoxantrone (MTZ) and Chlorin e6 (Ce6) due to its hollow structure and ability to release drugs in the acidic environments. Thus, the synergy of photodynamic therapy (PDT), photothermal therapy (PTT) and chemotherapy can induce the process of immunogenic cell death, stimulate the maturation of dendritic cells (DCs), and activate the immune response to kill tumor cells dramatically. Efficient immunotherapeutic effects were obtained when MnO2-C/M-HA was given intravenously to 4T1 tumor-bearing BALB/c mice with 660 nm near-infrared laser irradiation. This study overcame the limitations of monotherapy and provided a multifunctional platform for tumor immunotherapy.

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO2-x) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

Abstract. Background:. Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods:. Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results:. A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions:. The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

Flood-prone people and decision-makers are often unwilling to discuss and prepare for exceptional events, as such events are hard to perceive and out of experience for most people. Once an exceptional flood occurs, affected people and decision-makers are able to learn from this event. However, this learning is often focussed narrowly on the specific disaster experienced, thus missing an opportunity to explore and prepare for even more severe, or different, events. We propose spatial counterfactual floods as a means to motivate society to discuss exceptional events and suitable risk management strategies. We generate a set of extreme floods across Germany by shifting observed rainfall events in space and then propagating these shifted fields through a flood model. We argue that the storm tracks that caused past floods could have developed several tens of km away from the actual tracks. The set of spatial counterfactual floods generated contains events which are more than twice as severe as the most disastrous flood since 1950 in Germany. Moreover, regions that have been spared from havoc in the past should not feel safe, as they could have been badly hit as well. We propose spatial counterfactuals as a suitable approach to overcome society’s unwillingness to think about and prepare for exceptional floods expected to occur more frequently in a warmer world.

Abstract Breast cancer is one of the most-common female malignancies with a high risk of relapse and distant metastasis. The distant metastasis of breast cancer exhibits organotropism, including brain, lung, liver and bone. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells with tumor-initiating ability, which participate in regulating distant metastasis in breast cancer. We investigated the heterogeneity of BCSCs according to biomarker status, epithelial or mesenchymal status and other factors. Based on the classical “seed and soil” theory, we explored the effect of BCSCs on the metastatic organotropism in breast cancer at both “seed” and “soil” levels, with BCSCs as the “seed” and BCSCs-related microenvironment as the “soil”. We also summarized current clinical trials, which assessed the safety and efficacy of BCSCs-related therapies. Understanding the role of BCSCs heterogeneity for regulating metastatic organotropism in breast cancer would provide a new insight for the diagnosis and treatment of advanced metastatic breast cancer.

Abstract Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.

Introduction: Ischemic stroke (IS) is a common and severe neurological disorder and is associated with high rates of mortality and morbidity. Inflammatory reaction in astrocytes is one of the important pathological factors of stroke. Improved understanding of the underlying molecular mechanisms should aid better treatment of the disease. This study aimed to test our hypothesis that a miR-499a played an important role in the inflammatory response in astrocytes induced by IS targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Methods: This study was comprised of two models: oxygen-glucose deprivation (OGD) and reoxygenation model. Quantitative real-time PCR (qRT-PCR) and Western blot were used to examine gene expression levels, and MTT assay analysis were used to examine cell states. The relationships between miR-499a and PTEN were confirmed by luciferase reporter assay. Results: MiR-499a was robustly downregulated with OGD induced injury in astrocytes. Forced transient expression of miR-499a in OGD astrocytes nearly completely reversed the inflammatory response. Knockdown of miR-499a by its specific inhibitor in healthy astrocytes induced the inflammatory response resembling those produced by OGD. On the other hand, PTEN was markedly upregulated in OGD astrocytes, which was reciprocal to the expression of miR-499a. PTEN was experimentally validated as a direct target gene for miR-499a. Overexpression of PTEN was able to induce an inflammatory response of astrocytes. Moreover, PTEN siRNA counteracted the inflammatory response induced by OGD. Conclusions: Taken together, our findings indicate miR-499a as an important factor to prevent inflammatory response and suggest miR-499a as a new molecule for the treatment of IS. The present study also demonstrated the relationship between miR-499a and PTEN, with PTEN as a downstream signaling mediator of miR-499a in the inflammatory response of astrocytes induced by IS.

Study region: China Study focus: Water evaporation represents a pivotal indicator of the terrestrial ecosystem and hydrological cycle, influencing regional water and energy balance to some extent. In this study, the long-term data series of water surface evaporation (Ep) were assimilated across China, with the observations from 552 national benchmark weather stations. The trends of Ep and the influential climate variables were well detected. The analytical derivation method was built up to quantitatively attribute the effects from 5 key climate fields to Ep variations, including wind speed (u2), sunshine duration (n), relative humidity (RH), daily maximum (Tmax), and minimum (Tmin) air temperature. New hydrological insights for the region: The attribution results were more accurate and reasonable than those from two commonly used statistically based climate elasticity methods, which tended to overestimated the Ep variations. Most weather stations had experienced the decreasing trends of Ep during the entire research period of 1961–2018, which were mainly attributed to the decreasing in u2, n and RH, while the effects of regional warming (rising air temperature) were less influential on Ep variations at the long-term scale. The variations of Ep attributed to the three main influential climate variables (u2, n and RH) across China had also shown different temporal and spatial tendency patterns during different historical research periods. For example, the changing n and RH had shown increasing power on Ep variations in the western China climate zones. Comparatively, the u2 has been losing its power in decreasing Ep in most regions of China due to the slowdown in the declining rates of wind speed. This dynamic Ep attribution process is worthy of continuous focus and systematic research.

Purpose: To evaluate the impact of post-mastectomy radiation therapy (PMRT) in breast cancer patients with stage T4N0M0.Method: Patients diagnosed with breast cancer of T4N0M0 from Jan 2010 to Dec 2015 were extracted from SEER database. Multivariable logistic regression was used to analyze the factors associated with PMRT. Univariate and multivariate COX regression were used to analyze factors that might be associated with breast cancer specific survival (BCSS) and overall survival (OS) of patients. Kaplan–Meier analysis was performed to evaluate BCSS and OS in different subtypes of patients.Result: Multivariable logistic regression showed that patients ≥ 71 years were less intend to have PMRT. Multivariate Cox analysis showed that married statue, HR+/Her- and HR+/Her+ subtypes, were independent predictors of improved BCSS and OS, and use of PMRT could improve BCSS and OS . PMRT was beneficial for OS in all subtypes breast cancer patients, but BCSS benefit was observed only in TNBC patients.Conclusion: The use of PMRT improves OS in all T4N0M0 patients, but in terms of BCSS, it only beneficial for TNBC patients.

Treatment options are limited for patients with triple negative breast cancer (TNBC). Understanding genes that participate in cancer progression and DNA damage response (DDR) may improve therapeutic strategies for TNBC. DAXX, a death domain-associated protein, has been reported to be critically involved in cancer progression and drug sensitivity in multiple cancer types. However, its role in breast cancer, especially for TNBC, remains unclear. Here, we demonstrated a tumor suppressor function of DAXX in TNBC proliferation, colony formation, and migration. In Mouse Xenograft Models, DAXX remarkably inhibited tumorigenicity of TNBC cells. Mechanistically, DAXX could directly bind to the promoter region of RAD51 and impede DNA damage repair, which impacted the protection mechanism of tumor cells that much depended on remaining DDR pathways for cell growth. Furthermore, DAXX-mediated inefficient DNA damage repair could sensitize BRCA-proficient TNBC cells to PARP inhibitors. Additionally, we identified that dual RAD51 and PARP inhibition with RI-1 and ABT888 significantly reduced TNBC growth both in vitro and in vivo, which provided the first evidence of combining RAD51 and PARP inhibition in BRCA-proficient TNBC. In conclusion, our data support DAXX as a modulator of DNA damage repair and suppressor of TNBC progression to sensitize tumors to the PARP inhibitor by repressing RAD51 functions. These provide an effective strategy for a better application of PARP inhibition in the treatment of TNBC.

Abstract Inflammatory breast cancer (IBC) is an infrequent but aggressive manifestation of breast cancer, which accounts for 2–4% of all breast cancer cases but responsible for 7–10% of breast cancer-related deaths, and with a 20–30% 10-year overall survival compared with 80% for patients with non-IBC with an unordinary phenotype, whose molecular mechanisms are still largely unknown to date. Discovering and identifying novel bio-markers responsible for diagnosis and therapeutic targets is a pressing need. MicroRNAs are a class of small non-coding RNAs that are capable to post-transcriptionally regulate gene expression of genes by targeting mRNAs, exerting vital and tremendous affects in numerous malignancy-related biological processes, including cell apoptosis, metabolism, proliferation and differentiation. In this study, we review present and high-quality evidences regarding the potential applications of inflammatory breast cancer associated microRNAs for diagnosis and prognosis of this lethal disease.

Abstract Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics.

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double-strand-break marker γH2AX. On the other hand, combined treatment with AZD6738 and AZD1775 forces mitotic entry of cells with DNA damages by activating CDK1 activity, inducing severely aberrant mitosis and mitotic catastrophe, ultimately resulting in cell death. Dual inhibition of WEE1 and ATR also inactivated RAD51-mediated homologous recombination, which sensitized TNBC cells to cisplatin and PARP inhibitor. Here, based on the preclinical results that ATR inhibition synergizes with WEE1 inhibition in TNBC, we propose that this combination therapy alone, or in parallel with chemotherapy, represents an innovative and potent targeted therapy in TNBC.

Background/Aims: The targeted therapy for triple-negative breast cancer (TNBC) is still challenging due to poor understanding on its molecular etiology. The androgen receptor (AR) has recently emerged as a prognostic and treatment-predictive marker in breast cancer. However, the role of AR in TNBC remained elusive. Methods: Immunohistochemistry (IHC) was used to detect AR and G-protein coupled estrogen receptor (GPER) expression in tissue microarrays of 165 TNBC patients. Microarray analysis of mRNAs was performed to identify downstream regulators of AR. TNBC cells were cultured with dihydrotestosterone (DHT) alone or in combination with AR knockdown performed with AR shRNA. Cell viability and colony formation were assessed. Western blotting and qRT-PCR were used to examine protein and mRNA expression, respectively. The potential mechanism of AR-mediated GPER suppression was identified by Chromatin immunoprecipitation (ChIP) assay. AR and GPER expressions were also assessed in nude mouse xenografts by IHC. Results: IHC staining showed that the expression of AR was positively associated with tumor size, lymph node metastasis and high-grade tumor in TNBC patients. AR activation triggered by DHT suppressed GPER expression, to promote cell growth of TNBC. G-1, a GPER agonist, inhibited DHT-stimulated proliferation. Further experiments illustrated that AR suppressed GPER activation via binding directly to the promoter of GPER. Moreover, a negative correlation between AR and GPER was observed in MDA-MB-231 tumor cell xenografts and TNBC patient samples. Conclusions: The suppression of GPER via AR may be involved in the positive actions towards the TNBC progression, making it a promising therapeutic target for TNBC treatment.

Abstract Background Increasing evidence has indicated an important role for estrogen receptor beta 1 (ERβ1) in breast cancer. However, the role of ERβ1 in the metastasis of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) and the underlying mechanisms are still unknown. Methods Stable ERβ1-expressing TNBC cell lines were generated for this study. We detected the abilities of cell migration and invasion by wound-healing and transwell assays and the expression of E-cadherin and N-cadherin by quantitative RT-PCR (qRT-PCR) and western blotting assays in TNBC cell lines. Chromatin immunoprecipitation (ChIP) analysis was performed to assess the effect of AR on ERβ1 promoter. Tumor metastasis was evaluated in vivo using a lung metastasis mouse model. Lastly, immunohistochemical expression of ERβ1 in TNBC tissues was analyzed and correlated with clinicopathological features. Results ERβ1 suppressed the invasion and migration abilities of AR-positive TNBC cells and induced the downregulation of ZEB1. ZEB1 overexpression abrogated the increase in E-cadherin expression and the decrease in N-cadherin expression modulated by ERβ1. A lung metastasis mouse model showed that the incidence of metastasis was lower in ERβ1-expressing TNBC cells. Further, AR activation increased the anti-metastatic effect of ERβ1 in AR-positive TNBC cells, which accelerated ERβ1 transcription by functioning as a transcription factor that bound to the promoter of ERβ1. No significant change was observed in AR expression induced by ERβ1. Immunohistochemistry (IHC) analysis of TNBC clinical samples showed that ERβ1 and AR were positive in 31.7% and 23.2% of samples, respectively. ERβ1 expression was negatively correlated with ZEB1 expression and lymph node metastasis, and positively correlated with the expression of AR and E-cadherin. Conclusion Our findings suggested a potential role of ERβ1 in metastasis of AR-positive TNBC and provided novel insights into the mechanism of action of ERβ1 and the possible relationship between ERβ1 and AR.

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

In this study, 6 widely used precipitation products APHRODITE, CPC_UNI_PRCP, CN05.1, PERSIANN-CDR, Princeton Global Forcing (PGF), and TRMM 3B42 V7 (TMPA), were evaluated against gauge observations (CMA data) from 1998 to 2014, and applied to streamflow simulation over the Upper Yellow River basin (UYRB), using 4 hydrological models (DWBM, RCCC-WBM, GR4J, and VIC). The relative membership degree (u), as the comprehensive evaluation index in the hydrological evaluation, was calculated by the optimum fuzzy model. The results showed that the spatial pattern of precipitation from the CMA dataset and the other 6 precipitation products were very consistent with each other. The satellite-derived rainfall products (SDFE), like PSERSIANN-CDR and TMPA, depicted considerably finer and more detailed spatial heterogeneity. The SDFE and reanalysis (RA) products could estimate the monthly precipitation very well at both gauge and basin-average scales. The runoff simulation results indicated that the APHRODITE and TMPA were superior to the other 4 precipitation datasets, obtaining much higher scores, with average u values of 0.88 and 0.77. The precipitation estimation products tended to show better performance in streamflow simulation at the downstream hydrometric stations. In terms of performance of hydrological models, the RCCC–WBM model showed the best potential for monthly streamflow simulation, followed by the DWBM. It indicated that the monthly models were more flexible than daily conceptual or distributed models in hydrological evaluation of SDFE or RA products, and that the difference in precipitation estimates from various precipitation datasets were more influential in the GR4J and VIC models.

Aims: microRNA-101 (miR-101) is down-regulated in several cancers. In this study, we explored the effects of dysregulated miR-101 on breast cancer cells and the underlying mechanisms. Methods: miR-101 level was quantified by real-time RT-PCR. Cell viability was analyzed by MTT assay. Apoptosis was detected by flow cytometry and TUNEL assay. Moreover, the level of protein expression was determined by Western blot. Results: miR-101 level was markedly reduced in both the human breast cancer samples and cultured breast cancer cell lines (MCF-7, MDA-MB-231). Overexpression of miR-101 inhibited the proliferation and promoted the apoptosis in cultured MCF-7 and MDA-MB-231 cells, which were reversed by co-transfection of AMO-101, the inhibitor of miR-101. We validated Janus kinase 2 (Jak2) as a direct target of miR-101. Knockdown of Jak2 induced apoptosis in cultured breast cancer cells. Moreover, the level of miR-101 is negatively correlated with Jak2 in breast cancer tissues and cell lines. Conclusions: miR-101 suppressed proliferation and promoted apoptosis in breast cancer cells by targeting Jak2. These findings indicate that manipulation of miR-101 expression may represent a novel therapeutic strategy in the treatment of breast cancer.

BACKGROUND: A recent genome-wide association study (GWAS) has identified three new breast cancer susceptibility loci at 12p11, 12q24 and 21q21 in populations of European descent. However, because of the genetic heterogeneity, it is largely unknown for the role of these loci in the breast cancer susceptibility in the populations of non-European descent. METHODOLOGY/PRINCIPAL FINDINGS: Here, we genotyped three variants (rs10771399 at 12p11, rs1292011 at 12q24 and rs2823093 at 21q21) in an independent case-control study with a total of 1792 breast cancer cases and 1867 cancer-free controls in a Chinese population. We found that rs10771399 and rs1292011 were significantly associated with risk of breast cancer with per-allele odds ratios (ORs) of 0.85 (95% confidence interval (CI): 0.76-0.96; P = 0.010) and 0.84 (95% CI: 0.76-0.95; P = 4.50×10(-3)), respectively, which was consistent with those reported in populations of European descent. Similar effects were observed between ER/PR positive and negative breast cancer for both loci. However, we did not found significant association between rs2823093 and breast cancer risk (OR = 0.97, 95%CI = 0.76-1.24; P = 0.795). CONCLUSIONS/SIGNIFICANCE: Our results indicate that genetic variants at 12p11 and 12q24 may also play an important role in breast cancer development in Chinese women.

We assess the ability of a regional weather generator to represent the extremity of heavy precipitation events (HPEs) across spatial and temporal scales. To this end, we implement the multi-site non-stationary Regional Weather Generator (nsRWG) for the area of Germany and generate 100 sets of synthetic daily precipitation data spanning 72 years. The weather extremity index (WEI) and its recent cross-scale modification (xWEI) are applied to quantify the cross-scale extremity of synthetic and observed HPEs and to compare their distributions. The results show that the nsRWG excels in replicating the extremity patterns for almost all 7 durations (ranging from 1 to 7 days) considered. The frequency of small-scale 1-day rainfalls is however slightly overestimated. nsRWG aptly reproduces the potential influential areas of HPEs, whether of short or long duration. It is capable of generating precipitation events mirroring the extremity patterns observed during past disaster-causing HPEs in Germany, while simultaneously accommodating their variations. This study demonstrates the potential of the nsRWG for simulating HPE-related hazard and assessing flood risks. [ABSTRACT FROM AUTHOR]

After a flood disaster, the question often arises: "What could have happened if the event had gone differently?" For example, what would be the effects of a flood if the path of a pressure system and the precipitation field had taken a different trajectory? In this paper, we use alternative scenarios of precipitation footprints shifted in space, the so-called "spatial counterfactuals" to generate plausible but unprecedented events. We explore the spatial counterfactuals of the deadly July 2021 flood in the Ahr Valley, Germany. We drive a hydrological model of the Ahr catchment with precipitation fields of this event systematically shifted in space. The resulting discharge is used as a boundary condition for a high-resolution two-dimensional hydrodynamic model. We simulate changes in peak flows, hydrograph volumes, maximum inundation extent and depths and affected assets and compare them to the simulations of the actual event. We show that even a slight shift of the precipitation field by 15–25 km eastwards, which does not seem implausible due to orographic conditions, causes an increase in peak flows at the gauge Altenahr of about 32 % and of up to 160 % at the individual tributaries. Also, significantly larger flood volumes of more than 25 % can be expected due to this precipitation shift. This results in significantly larger inundation extents and maximum depths at a number of analyzed focus areas. For example, in the focus area around Altenahr, the increase of mean and maximum depth of up to 1.25 m and 1.75 m, respectively, is simulated. The presented results should encourage flood risk managers as well as the general public to meet precautionary measures for extreme and unprecedented events. [ABSTRACT FROM AUTHOR]