Triple negative breast cancer (TnBc) is one of the most aggressive types of breast cancer and has a poor prognosis. Therefore, the development of novel drugs and understanding the molecular mechanisms that may contribute to the initiation and development of TnBc are urgently required. chidamide, a histone deacetylase inhibitor, has been reported as possessing anti-cancer properties in several cancers, however, the function of chidamide in TnBc remains to be elucidated. The present study revealed that chidamide inhibited the proliferation, colony formation and migration of TnBc cells. experiments investigating the underlying mechanism revealed that chidamide upregulated the expression of microrna (mir)-33a-5p in TnBc cells via rT-qPcr. luciferase reporter assay demonstrated that mir-33a-5p was bound to the 3'-untranslated region of lactate dehydrogenase a (ldHa) and decreased the expression of ldHa in TnBc cells. in addition, chidamide suppressed the expression of LDHA and significantly decreased the glycolysis of TNBC cells. collectively, the results of the present study demonstrated that chidamide reprogramed glucose metabolism, partially by targeting the mir-33a-5p/ldHa pathway, in TnBc. These findings indicate that chidamide may be a promising novel drug in the treatment of patients with TnBc.
Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor outcome. The discovery that dysregulated microRNAs (miRNAs) play an important role in tumor progression has led to the suggestion that miRNAs (miRs) could be a potential target for the treatment of TNBC. In the present study, it was demonstrated that miR-598 expression was significantly decreased in TNBC tissues and was related to the degree of lymph node metastasis of patients with TNBC. Ectopic expression of miR-598 suppressed viability and colony formation, as well as increased the apoptosis of TNBC cells. To further understand the functional mechanism of action underlying miR-598 in TNBC, targets of miR-598 were predicted with the miRDB bioinformatics tool. Jagged 1 (JAG1) was identified as a direct target of miR-598, possessing a binding site for miR-598 in its 3'-untranslated region. Overexpression of miR-598 inhibited the expression of JAG1 in TNBC cells. In addition, JAG1 was highly expressed in TNBC tissues and its expression was negatively correlated with the expression of miR-598. Overexpression of JAG1 significantly attenuated the inhibitory effects of miR-598 on the proliferation and colony formation of TNBC cells. Collectively, these results provided novel insights into the functional mechanism of action for the miR-598/JAG1 pathway in the development of TNBC.
Background: Since lobaplatin (LBP) has been approved to treat metastatic breast cancer in China, this study aimed to evaluate the safety and efficacy of LBP-based chemotherapy in clinical practice. Methods: This trial was a prospective, open-label, multicenter phase IV clinical trial that enrolled patients with unresectable locally advanced or recurrent/metastatic breast cancer from 34 sites between July 2013 and March 2017. Patients were treated with LBP monotherapy or in combination for four to six cycles. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: A total of 1179 patients were analyzed; 59 (5.0%) were treated with LBP alone, 134 (11.4%) with LBP plus paclitaxel, 263 (22.3%) with LBP plus docetaxel, 237 (20.1%) with LBP plus gemcitabine, 403 (34.2%) with LBP plus vinorelbine, and 83 (7.0%) with other LBP-based regimens. The overall incidence of adverse events (AEs) was 95.2%, and 57.9% of patients had grade >3 AEs. The most common grade >3 AEs were neutropenia (43.9%), leukopenia (39.4%), anemia (17.8%), and thrombopenia (17.7%). LBP monotherapy showed the lowest incidence of grade >3 AEs (39.0%), followed by LBP plus docetaxel (52.9%), LBP plus paclitaxel (59.0%), LBP plus vinorelbine (62.5%), and LBP plus gemcitabine (62.9%). The ORR and DCR were 36.8 and 77.0%, respectively. The median PFS was 5.5 months (95% confidence interval: 5.2–5.9). Conclusion: LBP-based chemotherapy shows favorable efficacy in patients with advanced breast cancer, with manageable safety profile. Trial registration: This trial was registered with ChiCTR.org.cn, ChiCTR-ONC-13003471.
Background: Unlike other subtypes of breast cancer, triple negative breast cancer (TNBC) exhibits aggressive and metastatic behaviors and a lack of effective targeted therapeutics. (R)-9bMS, a small-molecule inhibitor of the non-receptor tyrosine kinase 2 (TNK2), significantly inhibited TNBC cell growth; however, the functional mechanism of (R)-9bMS in TNBC remains largely unknown. background: Unlike other subtypes of breast cancer, triple negative breast cancer (TNBC) exhibits aggressive and high metabolic behaviors, and lack of effective targeted therapeutics. The small molecule inhibitor of the non-receptor tyrosine kinase TNK2, (R)-9bMS significantly inhibited TNBC cell growth, however, the functional mechanism of (R)-9bMS in TNBC remains largely unknown. Objective: The objective of this study is to explore the functional mechanism of (R)-9bMS in TNBC. objective: Explore the functional mechanism of (R)-9bMS in TNBC Methods: Cell proliferation, apoptosis and xenograft tumor growth assays were performed to evaluate the effects of (R)-9bMS on TNBC. The expression levels of miRNA and protein were detected by RT-qPCR or western blot, respectively. Protein synthesis was determined by analyzing the polysome profile and 35S-met incorporation. method: Cell proliferation, apoptosis and xenograft tumor growth assay was performed to evaluate the effects of (R)-9bMS on TNBC. miRNA and protein expression were detected by RT-qPCR or western blot, respectively. Protein synthesis was determined by polysome profile and 35S-met incorporation assays. Results: (R)-9bMS attenuated TNBC cell proliferation, induced cell apoptosis, and inhibited xenograft tumor growth. Mechanism study indicated that (R)-9bMS upregulated the expression of miR-4660 in TNBC cells. The expression of miR-4660 is lower in TNBC samples than that of the non-cancerous tissues. miR-4660 overexpression inhibited TNBC cell proliferation by targeting the mammalian target of rapamycin (mTOR), which reduced mTOR abundance in TNBC cells. Consistent with the down-regulation of mTOR, exposure of (R)-9bMS inhibited the phosphorylation of p70S6K and 4E-BP1, which consequently interrupted the total protein synthesis and autophagy of TNBC cells. result: (R)-9bMS attenuated TNBC cell proliferation, induced cell apoptosis, and inhibited xenograft tumor growth. Mechanism study indicated that (R)-9bMS upregulated the expression of miR-4660 in TNBC cells. miR-4660 is lower expressed in TNBC samples than that of the non-cancerous tissues. miR-4660 overexpression inhibited TNBC cell proliferation by targeting mTOR, which reduced mTOR abundance in TNBC cells. Consistent with the down-regulation of mTOR, (R)-9bMS exposure inhibited the phosphorylation of p70S6K and 4E-BP1, which consequently interrupted the total protein synthesis and autophagy of TNBC cells. Conclusion: These findings uncovered the novel working mechanism of (R)-9bMS in TNBC by attenuating mTOR signaling via up-regulating miR-4660. The potential clinical significance of (R)-9bMS in TNBC treatment is interesting to explore. other: none
Background Those living with metastatic breast cancer (MBC) have distinct and shifting concerns in regard to education and decision making in considering clinical trials as a treatment option. Clinical trials designs, are becoming increasingly complex, and many patients have concerns for biomarker requirements Aims/Research Questions · What is the status of MBCA advocacy members' and partners' digital information, education and access to metastatic breast cancer trials? · What plans do MBCA members/partners have for the next 6-18 months to educate and inform their constituents for the 2018 rollout of BreastCancerTrials.org's (BCT)Metastatic Trial Search (MTS) and Metastatic Trial Talk (MTT) and other trial matching systems? · What are the top 5 barriers regarding trial enrollment? · What are best practices for MBC trial education? Research Methodology and Design A comprehensive analysis was conducted comprising both secondary and primary research to inform these specific aims. Secondary research was conducted using previous capture of MBCA online digital resources and strengthened to include additional research on MBCA members and partners online resources including pages specifically devoted to clinical trials and metastatic clinical trials. Mixed methods approaches include: 1) An assessment of MBCA members' and partners' digital media presence regarding MBC trials using a standardized form and rating system, and an analysis of MBCA members 2017 use of MTS using BCT secondary data; 2) Structured, recorded interviews with selected MBCA members/ partners, sharing the results of the assessments and querying them regarding their future plans and perceived barriers; and 3) Mixed methods analyses of the interview recordings using DeDoose to assess and articulate key trends and perceptions. Statistical Methods Simple frequency percentages and means were used in the assessment rankings of the MBCA members. DeDoose was used to provide mixed method analyses of the MBCA member and partner interviews. Results Analysis of the MBCA members and partners websites and digital media showed that, increasingly, both groups use the full variety of digital media to educate their constituents regarding MBC clinical trials. The 13 MBCA advocacy members providing online access to BreastCancerTrials' MTS in 2017 provided 97% of the traffic to the MTS trial matching service. System types accessing the MTS widget were 57.3% desktops, 28.6% mobile devices and 14% tablets. Table 1 shows assessment totals of 5 categories of the 13 MBCA advocacy group members' websites using MTS as compared to the 19 MBCA members not using the widget. Table 2 shows the 2017 usage of BCT's MTS with 97% of the page views coming from MBCA members. Table 1.Assessment Ratings of MBCA Advocacy Partners on Metastatic Trial Education/AccessAwareness of Trials (e.g. explains trial Phases)Knowledge SharingInterest in Metastatic Breast CancerAction Potential for clinical trial access or enrollmentTotal (0-100)13 MBCA Advocate Members with MTS widget22.1523.0024.3124.1593.6219 MBCA Members without MTS widget13.2113.9513.5311.9552.16 Table 2.2017 Use Of Metastatic Trial SearchBCT's Metastatic Trial Search (MTS) Results2017Annual Page views33,360Unique Sessions14,295Show Trials8,100Show Trials by month675Average Time on Site (minutes)3:34Total Engagement Events5,006 Citation Format: Vollmer Dahlke DJ, Smith ML, Han G, Ory MG, Cohen E. Metastatic breast cancer alliance's patient education and access to trials: Perceptions and actions [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-14-03.
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