Long non-coding RNA MIDEAS-AS1 inhibits growth and metastasis of triple-negative breast cancer via transcriptionally activating NCALD.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear. METHODS: Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD. RESULTS: LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD. CONCLUSIONS: Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.

Adaptive Model Predictive Control for Mobile Robots with Localization Fluctuation Estimation.

Mobile robots are widely employed in various fields to perform autonomous tasks. In dynamic scenarios, localization fluctuations are unavoidable and obvious. However, common controllers do not consider the impact of localization fluctuations, resulting in violent jittering or poor trajectory tracking of the mobile robot. For this reason, this paper proposes an adaptive model predictive control (MPC) with an accurate localization fluctuation assessment for mobile robots, which balances the contradiction between precision and calculation efficiency of mobile robot control. The distinctive features of the proposed MPC are three-fold: (1) Integrating variance and entropy-a localization fluctuation estimation relying on fuzzy logic rules is proposed to enhance the accuracy of the fluctuation assessment. (2) By using the Taylor expansion-based linearization method-a modified kinematics model that considers that the external disturbance of localization fluctuation is established to satisfy the iterative solution of the MPC method and reduce the computational burden. (3) An improved MPC with an adaptive adjustment of predictive step size according to localization fluctuation is proposed, which alleviates the disadvantage of a large amount of the MPC calculation and improves the stability of the control system in dynamic scenes. Finally, verification experiments of the real-life mobile robot are offered to verify the effectiveness of the presented MPC method. Additionally, compared with PID, the tracking distance and angle error of the proposed method decrease by 74.3% and 95.3%, respectively.

Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib.

The application of lapatinib, a widely used dual inhibitor of human epidermal growth factor receptor 1 (EGFR/ERBB1) and 2 (HER2/ERBB2), has been seriously limited due to cutaneous toxicity. However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to the lack of an effective strategy to improve clinical safety. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and ultimately cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce an aberrant immune response and promote the release of inflammatory factors in vitro and in vivo. Mechanistically, downregulated expression of the DNA repair protein HMGB1 played a critical role in these toxic reaction processes. Overexpression of HMGB1 inhibited keratinocyte apoptosis and inflammatory reactions. Therefore, restoring HMGB1 expression might be an effective remedy against lapatinib-induced cutaneous toxicity. Finally, we found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent the toxicity of lapatinib in mice. Collectively, our study might bring new hope to clinicians and tumor patients and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.

Evaluation of Carbon Nanoparticle Suspension and Methylene Blue Localization for Preoperative Localization of Nonpalpable Breast Lesions: A Comparative Study.

Background: The resection of nonpalpable breast lesions (NPBLs) largely depends on the preoperative localization technology. Although several techniques have been used for the guidance of NPBL resection, more comfortable and effective methods are needed. This aim of this study was to evaluate the use and feasibility of carbon nanoparticle suspension (CNS) and methylene blue (MB)-guided resection of NPBL, to introduce alternative techniques. Methods: A total of 105 patients with 172 NPBLs detected by breast ultrasound were randomized to CNS localization (CNSL) group and MB localization (MBL) group. The injection times of the two groups were divided into 2, 4, 6, 12, 16, and 20 h before surgery. In this study, localization time, stained area, operation time, total resection volume (TRV), calculated resection ratio (CRR), and pathological diagnosis were assessed. Results: All of the 172 lesions were finally confirmed benign. Dye persisted in all cases in the CNSL group (109/109, 100%), while that persisted in only 53 cases in the MBL group (53/63, 84.1%) (P < 0.001). There was a significant correlation between dyeing time and dyeing area in the MBL group (r = -0.767, P < 0.001); however, there was no significant correlation in the CNSL group (r = -0.154, P = 0.110). The operation time was 11.05 ± 3.40 min in the CNSL group and 13.48 ± 6.22 min in the MBL group (P < 0.001). The TRV was 2.51 ± 2.42 cm3 in the CNSL group and 3.69 ± 3.24 cm3 in the MBL group (P = 0.016). For CRR, the CNSL group was lower than the MBL group (7.62 ± 0.49 vs. 21.93 ± 78.00, P = 0.018). There is no dye remained on the skin in the MBL group; however, dye persisted in 12 patients (19.4%) in the CNSL group (P = 0.001). Conclusion: Carbon nanoparticle suspension localization and MBL are technically applicable and clinically acceptable procedures for intraoperatively localizing NPBL. Moreover, given the advantages of CNSL compared to MBL, including the ability to perform this technique 5 days before operation and smaller resection volume, it seems to be a more attractive alternative to be used in intraoperative localization of NPBL.

Application of preoperative computed tomographic lymphography for precise sentinel lymph node biopsy in breast cancer patients.

BACKGROUND: In light of the extensive application of sentinel lymph node biopsy (SLNB) in clinically node-negative breast cancer patients and the recently investigated failure of SLNB after lumpectomy, it has become important to explore methods for preoperative mapping of sentinel lymph nodes (SLNs) and their lymphatics to direct precise SLNB and improve the identification rate of SLNs. METHODS: Twenty-seven patients with suspected breast cancer based on the results of the clinical examination and imaging were enrolled in the study. Computed tomographic lymphography (CTLG) followed by CT three-dimensional reconstruction was performed to determine the localization of SLNs and lymphatics on the body surface preoperatively. Intraoperatively combined staining with methylene blue and indocyanine green was used to evaluate the accuracy and feasibility of CTLG. RESULTS: SLNs and lymphatics from the breast were identified using CTLG in all patients, and preoperative SLNs and lymphatics localization on the body surface showed a significant role in the selection of operative incision and injection points. The accuracy rate of SLN and lymphatic detection by CTLG was 92.6% compared with intraoperatively combined staining. Moreover, preoperative CTLG performed well in SLN number detection, and the accuracy rate was 95.2%. CONCLUSION: We evaluate the procedure and application of preoperative CTLG in the superficial localization of SLNs and lymphatics, which may lead to a decreased incidence of cutting off the lymphatics of SLNs and consequently more rapid and accurate SLN detection. This method promotes personalized SLN mapping, providing detailed information about the number and anatomical location of SLNs and lymphatics for adequate surgical planning for breast cancer patients.

Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies.

Introduction: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.Areas covered: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.Expert opinion: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.

Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.

Identification and preservation of stained non-sentinel lymph nodes in breast cancer.

Sentinel lymph nodes (SLNs) are the first lymph nodes that receive lymphatic drainage from the breast. However, all stained lymph nodes are dissected as SLNs during surgery. The present study aimed to identify and preserve the stained non-SLNs and evaluate the safety during sentinel lymph node biopsy (SLNB) in breast cancer. SLNB was performed with a methylene blue and indocyanine green double-tracer technique. The first lymph node, which was connected with lymphatic vessels from the breast, was designated as the true SLN. The lymph node that was directly connected with the output lymphatic duct of the SLN was defined as post-SLN (poSLN), whereas the stained poSLN was designated as non-SLN. Both the stained SLN and non-SLN were sent to the pathological department for definitive diagnosis. The present study demonstrated that intraoperative dissection of the lymphatic network could distinguish true SLNs and stained non-SLNs. The number of stained lymph nodes was time-dependent. Not all stained lymph nodes were real SLNs, whereas the poSLNs would be stained if the staining time interval was inappropriate. The data indicated that the poSLNs were negative for metastasis when the SLNs were negative for metastasis. Stained lymph nodes may contain non-SLNs in addition to SLNs. Resection of all stained lymph nodes is not recommended. To reduce the morbidity due to SLNB complications, the identification and preservation of stained non-SLNs during SLNB is feasible and warrants further study in the era of precision medicine.

COVID-19 epidemic: a special focus on diagnosis, complications, and management.

INTRODUCTION: The outbreak of COVID-19 caused by SARS-CoV-2 infection has become a serious hazard to global health. Apart from attacking respiratory system, it can induce multiorgan dysfunction, including cardiovascular system, liver, kidney, gastrointestinal, nervous system, and immune system. However, there are few reviews focusing on summary and comparison of diagnostic methods and complications induced by SARS-CoV-2 infection, which places a significant limit on the effective management. AREAS COVERED: This review is a blend of evidence obtained by literature retrieval from PubMed, clinical experience, and the authors' opinions. We searched PubMed using the terms 'COVID-19 & diagnosis' and 'COVID-19 & complications' and selected the most relevant articles. Here we summarize the diagnostic methods that are available in clinic and discuss their different characters. Furthermore, the review offers an insight into the symptoms, incidence, and clinical strategies of complications associated with SARS-CoV-2 infection. EXPERT OPINION: COVID-19 has been a global pandemic, which requires rapid response. The comparison between different characters of the diagnostic methods and the summary of the symptoms, incidence, and clinical strategies of complications given in this review are not only significant for the optimal use of diagnostic methods, but also beneficial for the prevention and management of complications.

Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity. AREAS COVERED: Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery. EXPERT OPINION: Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.

Clinicopathological features of granulomatous lobular mastitis and mammary duct ectasia.

Granulomatous lobular mastitis (GLM) and mammary duct ectasia (MDE) are inflammatory diseases. However, only a limited number of studies have focused on characterizing their clinicopathological features. The aim of the present study was to investigate the etiology, clinicopathological characteristics and diagnosis of GLM and MDE. The clinical information and treatment of 118 female patients with pathologically-proven GLM or MDE were retrospectively analyzed in the present study. A total of 29 cases had GLM, 77 had MDE and 12 had GLM accompanied by MDE. GLM tends to occur in patients who have had their last birth within 5 years and are usually <40 years of age. GLM masses were usually larger than MDE masses and suppurated or ulcerated more easily. Histopathologically, GLM was characterized by a significant granulomatous inflammatory reaction centered on lobules. Compared with MDE, GLM had a higher incidence of granuloma and microabscess formation within the lobules and surrounding tissue. More multinucleated giant cells within granuloma were observed in patients with GLM than in those with MDE, while MDE was characterized by significant dilatation of the duct terminals and inflammatory changes in the duct wall and periductal tissues. When compared with patients with GLM, foam cells within the duct epithelium or surrounding stroma were more common in patients with MDE. The present study demonstrated that GLM and MDE had distinct clinicopathological characteristics. Further research is required in order to identify more appropriate treatment strategies for these specific types of breast inflammation.

Galactogram Grading System for Identifying Breast Cancer With Nipple Discharge.

BACKGROUND: Galactography is a primary recommendation in the management of nipple discharge (ND), which may be caused by benign or malignant lesions. We aimed to establish a galactogram grading system (GGS) and investigate its role in identifying breast cancer with ND. PATIENTS AND METHODS: A total of 350 patients were included in our study. All patients received preoperative mammographic galactography successfully and underwent surgery at Qilu Hospital of Shandong University between January 2011 and August 2015. We first performed a retrospective study in a consecutive series of 250 patients with ND to establish a GGS. Then the subsequent consecutive series of 100 patients was analyzed to validate the grading system. RESULTS: Our data showed that the GGS can well assess the risk of a galactogram's being malignant. Galactograms classified into grade I have a lower risk of being malignant, while those classified into grade III have a higher risk of being malignant. Thus, our GGS was useful for distinguishing malignant from benign lesions. CONCLUSION: We established a scoring system for breast disease with ND. This GGS may be a novel approach for identifying breast cancer with ND.

Langer's axillary arch lymph node metastasis in breast cancer patients: A prospective clinical study.

BACKGROUND AND OBJECTIVES: Latissimus dorsi, an anatomical landmark for axillary lymph node dissection, was reported to harbor an anatomical variation named Langer's axillary arch (LAA). However, the incidence and clinical significance of LAA in breast cancer remain obscure. METHODS: We conducted a six-year prospective study, including 1724 breast cancer patients in Qilu hospital between January 2012 to February 2018. All patients received ALND were inspected for existence of LAA. All the surgeries were completed with the involvement of same experienced surgeon. Once the LAA was identified, all the lymph nodes located lateral to it, named LAA's lymph node, were dissected and collected for pathologic examination. RESULTS: Among 1724 breast cancer patients, LAA was identified in 132 patients (7.66%). 120 out of the 132 patients (90.91%) had at least two LAA's lymph nodes. 21 out of 120 patients (17.50%) were confirmed with cancer cell metastasis in LAA's lymph nodes. Among the 23 patients received sentinel lymph node tracing, sentinel lymph node was located lateral to LAA in 3 patients (13.04%). CONCLUSIONS: Our results indicated that it is of great importance for surgeons to correctly ascertain LAA, and it should be taken as a nonnegligible parts during ALND or SLNB.

Relationship between Upper Extremity Lymphatic Drainage and Sentinel Lymph Nodes in Patients with Breast Cancer.

PURPOSE: The purpose of this study was to identify the relationship between upper extremity lymphatics and sentinel lymph nodes (SLNs) in breast cancer patients. METHODS: Forty-four patients who underwent axillary reverse mapping (ARM) during axillary lymph node dissection (ALND) with SNL biopsy (SLNB) between February 2017 and October 2017 were investigated. ARM was performed using indocyanine green (ICG) to locate the upper extremity lymphatics; methylene blue dye was injected intradermally for SLN mapping. RESULTS: ARM nodes were found in the ALND fields of all examined patients. The rate of identification of upper extremity lymphatics within the SLNB field was 65.9% (29 of 44). The ARM nodes were involved in metastases arising from primary breast tumors in 7 of the patients (15.9%), while no metastases were detected in pathologic axillary lymph node-negative patients. Lymphatics from the upper extremity drained into the SLNs in 5 of the 44 patients (11.4%); their ARM-detected nodes were found to be in close proximity to the SLNs. CONCLUSIONS: The ARM nodes and SLNs are closely related and share lymphatic drainage routes. The ARM procedure using fluorescence imaging is both feasible and, in patients who are SLN negative, oncologically safe. ARM using ICG is therefore effective for identifying and preserving upper extremity lymphatics, and SLNB combined with ARM appears to be a promising surgical refinement for preventing upper extremity lymphoedema. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrial.gov: NCT02651142.

Bisdemethoxycurcumin protects against renal fibrosis via activation of fibroblast apoptosis.

Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 µM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis.

MiR-770 suppresses the chemo-resistance and metastasis of triple negative breast cancer via direct targeting of STMN1.

Chemo-resistance and metastasis of triple negative breast cancer (TNBC) contributed the most of treatment failure in the clinic. MicroRNAs (miRNAs) have been proved to be involved in many biological processes and diseases. In this study, we aimed to determine the role of miR-770 in the regulation of chemo-resistance and metastasis of TNBC. Clinically, miR-770 was highly expressed in chemo-sensitive tissues and predicted a better prognosis of TNBC. Functionally, ectopic expression of miR-770 suppressed the doxorubicin-resistance of TNBC cell lines via regulation of apoptosis and tumor microenvironment, which was mediated by exosomes. Moreover, miR-770 overexpression inhibited the migration and invasion. Rescue of STMN1 could partly reverse the effect of miR-770 in TNBC behaviors. Furthermore, we also demonstrated that overexpression of miR-770 inhibited DOX resistance and metastasis in vivo. Taken together, our results proved that miR-770 could suppress the doxorubicin-resistance and metastasis of TNBC cells, which broaden our insights into the underlying mechanisms in chemo-resistance and metastasis, and provided a new prognostic marker for TNBC cells.

Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway.

BACKGROUND/AIMS: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression. METHODS: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL. RESULTS: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p. CONCLUSION: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

Precise intraoperative sentinel lymph node biopsies guided by lymphatic drainage in breast cancer.

The purpose of this study was to present a novel surgical method for intraoperative precise sentinel lymph node biopsy (SLNB) and to determine its clinical efficacy and sensitivity in breast cancer patients. The sentinel lymph nodes (SLNs) were preoperatively evaluated by axillary ultrasound. The intraoperative detection of SLNs was guided by lymphatic drainage pathway. The lymphatic vessels and SLNs were visualized. During operation, we searched for all the true SLNs (trSLNs), para-SLNs (paSLNs) and post-SLNs (poSLNs) followed lymphatic drainage ducts. After precisely locating the lymphatic channels and lymph node, all the lymph nodes that firstly receive lymphatic drainage are designated as trSLNs. We precisely distinguished the trSLNs, paSLNs and poSLNs. We found the average number of trSLNs ranged from1 to 6. In addition, we assessed the novel technique in a total of 125 breast cancer patients. trSLNs were successfully identified in all patients (detection rate: 100 %). The accuracy of trSLNs is 99.2%. Data from our study strongly suggest that our method is a feasible and effective for the detection of precise trSLNs in breast cancer with real-time observations. (ClinicalTrials.gov number, NCT02651142).

Huaier extract restrains the proliferative potential of endocrine-resistant breast cancer cells through increased ATM by suppressing miR-203.

Endocrine therapy is one of the main treatments for breast cancer patients in the early stages. Tamoxifen and fulvestrant are the major drugs of endocrine therapy for breast cancer patients. However, acquired drug resistance often caused treatment failure and relapse for patients, which is a major clinical problem. We investigated whether Huaier extract had effects on endocrine-resistant breast cancer cells. In our study, we aimed to demonstrate the inhibitory effects of Huaier extract on tamoxifen-resistant cells (M7-TR) and fulvestrant-resistant cells (M7-FR). Using MTT and clone formation assays, we found that Huaier extract could inhibit the proliferation in M7-TR and M7-FR cells. Flow cytometry and western blotting illustrated that Huaier extract could induce G0/G1 arrest in both endocrine-resistant breast cancer cells. Mechanistically, we present that Huaier extract significantly increased ataxia telangiectasia mutation (ATM) via down-regulation of miR-203. Huaier extract also had the inhibitory effects on tumour growth in vivo in a xenograft mouse model. These results demonstrated that Huaier extract could inhibit the proliferation of M7-TR and M7-FR cells by increasing ATM via suppression of miR-203.