Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) Derived from Bone Marrow Stromal Cells Promotes the Development of Triple-Negative Breast Cancer

2022 ◽  
Vol 12 (5) ◽  
pp. 1065-1070
Author(s):  
Jin Song ◽  
Jiahan Chang ◽  
Xue Lin ◽  
Cibo Fan ◽  
Lili Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phosphatase And Tensin Homolog ◽  
Vegf Signaling ◽  
Tensin Homolog ◽  
Tnbc Cell

Triple-negative breast cancer (TNBC) remains a threat to women’s life with a lack of targeted therapy. This study aimed to explore the role of PTEN derived from BMSCs in TNBC. We carried out a retrospective analysis of 65 TNBC patients and 30 healthy subjects from October 2016 to January 2021 with a 10-year follow up. PTEN expression in TNBC tissues and cells was determined by RTqPCR. Functional experiments were conducted to evaluate PTEN’s effect on TNBC cell biological behaviors using MTT assay and Transwell assay, as well as on PI3K-Akt-HIF-1α-VEGF signaling transduction. PTEN was up-regulated in TNBC tissues relative to healthy controls and it was negatively associated with the survival rate. In in vitro experiments, PTEN overexpression increased cell viability and invasion and knocking down of PTEN exerted opposite effect. The expression of PI3K was directly regulated by PTEN. Up-regulation of PTEN resulted in a decline in HIF-1α, Akt and VEGF expressions, which were elevated after knocking down of PTEN. In conclusion, PTEN derived from BMSCs promotes TNBC cell development through blocking PI3K-Akt-HIF-1α-VEGF signaling pathway, providing a new theoretical basis for targeted therapy of TNBC.

scholarly journals Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

2016 ◽  
Vol 38 (3) ◽  
pp. 1003-1014 ◽  
Author(s):  
Aiyu Zhu ◽  
Yan Li ◽  
Wei Song ◽  
Yumei Xu ◽  
Fang Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative

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.

scholarly journals MicroRNA-1246 Suppresses the Metastasis of Breast Cancer Cells by Targeting the DRAK1A/PGRN Axis to Prevent the Epithelial-Mesenchymal Transition

2021 ◽  
Author(s):  
Pan Wang ◽  
Wenju Chen ◽  
Yaqiong Zhang ◽  
Qianyi Zhong ◽  
Zhaoyun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell ◽  
Novel Target

Abstract Objective. Breast cancer is one of the most common malignant and highly heterogeneous tumors in women. MicroRNAs (miRNAs), such as miR-1246, play important roles in various types of malignant cancers, including triple-negative breast cancer (TNBC). However, the biological role of miR-1246 in TNBC has not yet been fully elucidated. In this study, we studied the role of miR-1246 in the occurrence and development of TNBC and its mechanism of action.Methods. Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays were performed to observe the effects of miR-1246 on TNBC cell proliferation, migration, and invasion, respectively. The expression of epithelial-mesenchymal transition (EMT) markers was detected by western blotting. Dual luciferase reporter assays were performed to determine whether DYRK1A is a novel target of miR-1246. In addition, an immunoprecipitation experiment was performed to verify the binding of DYRK1A to PGRN. Rescue experiments were performed to determine whether DYRK1A is a novel target of miR-1246 and whether miR-1246 suppresses the metastasis of breast cancer cells by targeting the DRAK1A/PGRN axis to prevent the epithelial-mesenchymal transition.Results. Our results show that miR‑1246 suppresses the proliferation, migration, and invasion of TNBC cells and that DYRK1A is a novel target of miR-1246. MiR‑1246 plays a suppressive role in the regulation of the EMT of TNBC cells by targeting DYRK1A. DYRK1A mediates the metastasis of triple-negative breast cancer via activation of the EMT. We identified PGRN as a novel DYRK1A-interacting protein. DYRK1A and PGRN act together to regulate the occurrence and development of breast cancer through miR-1246.Conclusion. miR-1246 attenuates TNBC cell invasion and the EMT by targeting the DRAK1A/PGRN axis. Our data suggest that miR‑1246 may be used to develop novel early-stage diagnostic and therapeutic strategies for TNBC.

CTNND1 to mediate bone metastasis of triple-negative breast cancer via regulating CXCR4.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13045-e13045
Author(s):  
Chang Gong ◽  
Qun Lin ◽  
Xiaolin Fang ◽  
Wenguo Jiang ◽  
Jun Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
High Throughput ◽  
Triple Negative Breast Cancer ◽  
High Throughput Sequencing ◽  
Triple Negative ◽  
Mtor Pathway ◽  
Tissue Samples

e13045 Background: Compared to lumial breast cancer, the proporation of triple-negative breast cancer (TNBC) with bone metastases (BMs) is relatively low and few data focusing on the mechanism of the BMs in TNBC are available, Here, we screened that CTNND1 was associated with BMs of TNBC by integrating high-throughput sequencing, and further investigated the role of CTNND1 in BMs of TNBC in vitro. Methods: TNBC tissue samples with only BMs (n = 6) and without any metastasis (n = 10) were tested using high-throughput sequencing and 11 differentially expressed relative genes were identified. We then quantified these 11 genes in normal breast tissue samples (n = 26), TNBC tissue samples with only BMs (n = 10), TNBC tissue samples without any metastasis (n = 88) as well as luminal tissue samples with BMs（n = 10）through qPCR and immunohistochemical staining (IHC). The effects of knocking down CTNND1 on the interaction between TNBC cells and osteoblasts were examined by cell adhesion, transwell migration and matrigel invasion assays. To explorethe role of CTNND1 in mediating bone metastasis in TNBC, we used RNA-sequencing to find out the relative downstream gene CXCR4 and PI3K-AKT-mTOR pathway and verified it in vitro by Western Blotting. Results: Combining our high-throughput sequencing data, qPCR and IHC in clinical tissue samples, we verified that CTNND1 was decreased in TNBC patients with bone metastasis compared to normal tissue and luminal tissue with BMs. Knocking down of CTNND1 in TNBC cells including MDA-MB-231, MDA-MB-468 and BT549 weakened cells adhesion, but facilitated cells migration and invasion. Mechanically, knocking down of CTNND1 upregulated CXCR4 via activating PI3K-AKT-mTOR pathway in TNBC but not luminal and HER2- positive breast cancer cells lines. Conclusions: CTNND1 mediates bone metastasis in triple-negative breast cancer via regulating CXCR4.CTNND1 may serve as a potential predictor of bone metastasis for TNBC patients.

Rad51 Silencing with siRNA Delivered by Porous Silicon-Based Microparticle Enhances the Anti-Cancer Effect of Doxorubicin in Triple-Negative Breast Cancer

2021 ◽  
Vol 17 (12) ◽  
pp. 2351-2363
Author(s):  
Zeliang Wu ◽  
Lin Zhu ◽  
Junhua Mai ◽  
Haifa Shen ◽  
Rong Xu
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Porous Silicon ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Due to its high heterogeneity and aggressiveness, cytotoxic chemotherapy is still a mainstay treatment for triple negative breast cancer. Unfortunately, the above mentioned has not significantly ameliorated TNBC patients and induces drug resistance. Exploring the mechanisms underlying the chemotherapy sensitivity of TNBC and developing novel sensitization strategies are promising approaches for improving the prognosis of patients. Rad51, a key regulator of DNA damage response pathway, repairs DNA damage caused by genotoxic agents through “homologous recombination repair.” Therefore, Rad51 inhibition may increase TNBC cell sensitivity to anticancer agents. Based on these findings, we first designed Rad51 siRNA to inhibit the Rad51 protein expression in vitro and evaluated the sensitivity of TNBC cells to doxorubicin. Subsequently, we constructed discoidal porous silicon microparticles (pSi) and encapsulated discoidal 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes/siRad51 (PS-DOPC/siRad51) to explore the synergistic antitumor effects of siRad51 and doxorubicin on two mouse models of TNBC in vivo. Our in vitro studies indicated that siRad51 enhanced the efficacy of DOX chemotherapy and significantly suppressed TNBC cell proliferation and metastasis. This effect was related to apoptosis induction and epithelial to mesenchymal transition (EMT) inhibition. siRad51 altered the expression of apoptosis- and EMT-related proteins. In orthotopic and lung metastasis xenograft models, the administration of PS-DOPC/siRad51 in combination with DOX significantly alleviated the primary tumor burden and lung metastasis, respectively. Our current studies present an efficient strategy to surmount chemotherapy resistance in TNBC through microvector delivery of siRad51.

Co-loading of an anthracycline analogue Pirarubicin and Salinomycin in a 1:3 ratio into Quatramerbiodegradable polymeric nanoparticles synergistically inhibit growth of triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15047-e15047
Author(s):  
Surender Kharbanda ◽  
Anees Mohammad ◽  
Sachchidanand Tiwari ◽  
Neha Mehrotra ◽  
Sireesh Appajosyula ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancers ◽  
Mice Model ◽  
Single Drug ◽  
Tnbc Cell ◽  
Dual Drug

e15047 Background: Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and differ from other types of invasive breast cancers in that they grow and spread faster. TNBCs have limited treatment options and a worse prognosis. Therapy with anthracyclines considered to be one of the most effective agents in the treatment. Unfortunately, resistance to anthracycline therapy is very common due to drug efflux mediated by overexpression of ABC transporter. Pirarubicin (PIRA), an analogue of doxorubicin (DOX), is approved in Japan, Korea and China and is shown to be less cardiotoxic than DOX. Recent studies suggest that cancer stem cells (CSCs) play an important role in tumorigenesis and biology of TNBC. Targeting CSCs may be a promising, novel strategy for the treatment of this aggressive disease. Recent studies have shown that salinomycin (SAL) preferentially targets the viability of CSCs. Methods: SAL and PIRA were co-encapsulated in polylactic acid (PLA)-based block copolymeric nanoparticles (NPs) to efficiently co-deliver these agents to treat TNBC cells. Results: Generated SAL-PIRA co-encapsulated dual drug-loaded NPs showed an average diameter of 110 ± 7 nm, zeta potential of -12.5 mV and PDI of less than 0.25. Both of these anti-cancer agents showed slow and sustained release profile in non-physiological buffer (PBS, pH 7.4) from these dual drug-encapsulated NPs. Additionally, multiple ratios (PIRA:SAL = 3:1, 1:1, 1:3) were encapsulated to generate diverse dual drug-loaded NPs. The results demonstrate that, in contrast to 1:1 and 3:1, treatment of TNBC cells with 1:3 ratio of PIRA:SAL dual drug-loaded NPs, was associated with significant inhibition of growth in vitro in multiple TNBC cell lines. Interestingly, PIRA:SAL (1:3) was synergistic as compared to either SAL- or PIRA single drug-loaded NPs. The IC50 of PIRA and SAL in single drug-encapsulated NPs is 150 nM and 700 nM respectively in MDA-MB-468. Importantly, the IC50 of PIRA in dual drug-encapsulated NPs dropped down to 30 nM (5-fold). Similar results were obtained in SUM-149 TNBC cell line. Studies are underway to evaluate in vivo biological activity of PIRA:SAL (1:3) on tumor growth in a TNBC xenograft mice model. Conclusions: These results demonstrate that a novel dual drug-loaded NP formulation of PIRA and SAL in a unique ratio of 1:3 represents an approach for successful targeting of CSCs and bulk tumor cells in TNBC and potentially other cancer types.

scholarly journals LncRNA PAPAS may promote triple-negative breast cancer by downregulating miR-34a

2019 ◽  
Vol 47 (8) ◽  
pp. 3709-3718 ◽  
Author(s):  
Yan Kong ◽  
Cuizhi Geng ◽  
Qian Dong
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Cancer Biology ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Cancer Cell Proliferation ◽  
Healthy Controls ◽  
Plasma Samples

Objective To investigate the role of promoter and pre-rRNA antisense (PAPAS) long noncoding (Lnc) RNA in cancer biology. Methods Tumour and tumour-adjacent healthy tissue biopsies from patients with triple-negative breast cancer (TNBC), and plasma samples from these patients plus healthy controls, were assessed for PAPAS and microRNA (miR)-34a. Effects of PAPAS and miR-34a overexpression were also investigated in vitro. Results PAPAS was upregulated in tumour tissues of patients with TNBC versus tumour-adjacent healthy tissues. Plasma PAPAS levels were also upregulated in patients with TNBC versus healthy controls. Levels of PAPAS in tumour tissue was significantly positively correlated with PAPAS levels in plasma from patients with TNBC. MiR-34a was downregulated in tumour tissues versus adjacent healthy tissues, and was significantly correlated with PAPAS in tumour tissues. PAPAS overexpression in vitro was associated with miR-34a inhibition, while miR-34a failed to significantly affect PAPAS levels. PAPAS overexpression promoted in vitro migration and invasion of TNBC cells, while miR-34a overexpression was inhibitory. MiR-34a overexpression decreased the enhanced cell migration and invasion associated with PAPAS overexpression. PAPAS overexpression showed no significant effects on cancer-cell proliferation. Conclusion LncRNA PAPAS may promote TNBC by downregulating miR-34a.

scholarly journals Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Cui-Cui Zhao ◽  
Jing Chen ◽  
Li-Ying Zhang ◽  
Hong Liu ◽  
Chuan-Gui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Proliferation And Apoptosis

Abstract Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

scholarly journals PFKFB4 Overexpression Facilitates Proliferation by Promoting the G1/S Transition and Is Associated with a Poor Prognosis in Triple-Negative Breast Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yu-Chen Cai ◽  
Hang Yang ◽  
Hong-Bo Shan ◽  
Hui-Fang Su ◽  
Wen-Qi Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Signaling Networks ◽  
Oncogenic Signaling ◽  
Tnbc Cell ◽  
Key Factor ◽  
Tissue Specimens

Background. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphate-4 (PFKFB4) is a key factor that plays an important role in tumorigenesis. However, its role in triple-negative breast cancer (TNBC) progression needs to be further validated. We investigated whether PFKFB4 is directly involved in the oncogenic signaling networks of TNBC. Methods. First, we assessed the expression level of PFKFB4 in tumor tissue specimens by immunohistochemistry and evaluated its prognostic value. Next, the effect of PFKFB4 on TNBC cell growth and associated mechanisms were investigated. Finally, the results were further verified in vivo. Results. We found that PFKFB4 overexpression was associated with an unfavorable prognosis in TNBC patients. PFKFB4 was overexpressed in TNBC cell lines in hypoxic environments, and its overexpression promoted tumor progression in vitro and in vivo. Further analyses demonstrated that the possible mechanism might be that PFKFB4 overexpression facilitates TNBC progression by enhancing the G1/S phase transition by increasing the protein level of CDK6 and phosphorylation of Rb. Conclusions. These data suggest that PFKFB4 plays significant roles in the tumorigenesis and development of TNBC.

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