scholarly journals The AXL-PYK2-PKCα axis as a nexus of stemness circuits in TNBC

2021 ◽  
Vol 4 (6) ◽  
pp. e202000985
Author(s):  
Lohit Khera ◽  
Yaron Vinik ◽  
Flavio Maina ◽  
Sima Lev
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Transcription Factors ◽  
Feedback Loops ◽  
Breast Cancer Patients ◽  
Lysosomal Compartment ◽  
Tnbc Cell ◽  
Convergence Point ◽  
Basal Like Breast Cancer

Cancer stem cells (CSCs) are implicated in tumor initiation, metastasis and drug resistance, and considered as attractive targets for cancer therapy. Here we identified a clinically relevant signaling nexus mediated by AXL receptor, PYK2 and PKCα and show its impact on stemness in TNBC. AXL, PYK2, and PKCα expression correlates with stemness signature in basal-like breast cancer patients, and their depletion in multiple mesenchymal TNBC cell lines markedly reduced the number of mammosphere-forming cells and cells harboring CSCs characteristic markers. Knockdown of PYK2 reduced the levels of AXL, PKCα, FRA1, and PYK2 proteins, and similar trend was obtained upon PKCα depletion. PYK2 depletion decreased AXL transcription through feedback loops mediated by FRA1 and TAZ, whereas PKCα inhibition induced redistribution of AXL to endosomal/lysosomal compartment and enhanced its degradation. PYK2 and PKCα cooperate at a convergence point of multiple stemness-inducing pathways to regulate AXL levels and concomitantly the levels/activation of STAT3, TAZ, FRA1, and SMAD3 as well as the pluripotent transcription factors Nanog and Oct4. Induction of stemness in TNBC sensitized cells to PYK2 and PKCα inhibition suggesting that targeting the AXL-PYK2-PKCα circuit could be an efficient strategy to eliminate CSCs in TNBC.

scholarly journals LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2644
Author(s):  
Brianne M. Cruickshank ◽  
Marie-Claire D. Wasson ◽  
Justin M. Brown ◽  
Wasundara Fernando ◽  
Jaganathan Venkatesh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Gene Regulation ◽  
Cancer Stem Cells ◽  
Triple Negative ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mammosphere Formation ◽  
Basal Like Breast Cancer ◽  
Myosin Va

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

miRNAs as modulators of cholesterol in breast cancer stem cells: an approach to overcome drug resistance in cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Bernice Monchusi ◽  
Mandeep Kaur
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Disease Free Survival ◽  
Cancer Drug ◽  
Tumour Mass ◽  
Breast Cancer Patients ◽  
Cancer Drug Resistance ◽  
Related Drug

: It has been postulated that a small number of cancer stem cells (CSCs) buried in tumour mass drive cancer growth and impart cancer drug resistance. However, their eradication has not been achieved so far as the mechanistic understanding around CSCs’ role in cancer development and growth is limited. The cholesterol accumulation and efflux processes have been shown to play an important role in maintaining cell’s integrity and its sensitivity towards drugs, as altered cholesterol pathways contribute to cancer drug resistance. Emerging evidences have indicated miRNAs as regulators of CSCs, and also as regulators of cholesterol pathways in cancer cells, but a link between the two has not been fully established so far. In this review, we have collated key signalling pathways, and published evidences emphasising the involvement of miRNAs and cholesterol in CSCs related drug resistance. Additionally, we have used bioinformatics analysis to identify miRNAs that may modulate cholesterol pathways in CSCs at molecular level to contribute to cancer drug resistance. Our results that two miRNAs (hsa-miR-34a-5p and hsa-miR-373-3p) interact, and bind to two known Breast CSC markers (CD44 and CD24), and mediate expression of several cholesterol-related genes (INSIG2, APOL2, CYP51A1, HDLB, and DHCR7). Furthermore, survival analysis of the breast cancer patients’ gene expression data revealed that higher expression of these genes is associated with poor disease free survival. We therefore propose that targeting these two miRNAs could possibly provide a way to alter cell’s response to drugs via modulating cholesterol pathway in CSCs.

scholarly journals Long Non-Coding RNA ANRIL Promotes Doxorubicin Resistance in Triple-Negative Breast Cancer via Suppressing Glycolysis Through the MicroRNA-125a/ENO Pathway

2021 ◽  
Author(s):  
Jianli Ma ◽  
Wenhui Zhao ◽  
Han Zhang ◽  
Zhong Chu ◽  
Huili Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Active Role ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Tnbc Cell

Abstract BackgroundBreast cancer is the main cause of death among women worldwide. More and more long non-coding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors during cancer development. However, whether ANRIL is involved in drug resistance in triple-negative breast cancer (TNBC) has not been investigated. MethodsLuciferase reporter assay was conducted to verify the binding of miR-125a and ANRIL. RT-PCR and western blot were performed to detect the expression of miR-125a, ANRIL and ENO1. Gene silence and overexpression experiments as well as CCK-8 and colony formation assays on TNBC cell lines were performed to determine the regulation of molecular pathways. Glycolysis analysis was performed with Seahorse extracellular flux methodology. ResultsANRIL expression in TNBC patients and TNBC cells was examined and we found that ANRIL expression was upregulated in both TNBC patients and TNBC cell lines. Knockdown of ANRIL increased the cytotoxic effect of ADR and inhibited HIF-1α-dependent glycolysis in TNBC cells. In addition, we found that ANRIL negatively regulated miR-125a expression in TNBC cell lines. Besides, a dual-luciferase reporter assay proved ANRIL functioned as a sponger of miR-125a. Further investigation revealed that ENO1 was a target of miR-125a and positively regulated by ANRIL in TNBC cells. Additionally, ANRIL upregulation reversed miR-125-mediated inhibition on HIF-1α-dependent glycolysis in TNBC cells. More notably, 2-deoxy-glucose (2-DG) attenuated ANRIL-induced increase of drug resistance in TNBC cells. ConclusionsTaken together, our study was the first to identify that knockdown of ANRIL plays an active role in overcoming the drug resistance in TNBC by inhibiting glycolysis through the miR-125a/ENO1 pathway, which maybe serve useful for the development of novel therapeutic targets.

scholarly journals Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide

2021 ◽  
Author(s):  
Patricia Cámara-Sánchez ◽  
Zamira V. Díaz-Riascos ◽  
Natalia García-Aranda ◽  
Petra Gener ◽  
Joaquin Seras-Franzoso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Subtype ◽  
Anchorage Independent Growth ◽  
Tnbc Cell

Abstract Background Cancer maintenance, metastatic dissemination and drug-resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest numbers of CSCs and poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. Methods The anti-CSC efficacy of up to 17 small-drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness hallmarks were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes upon 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on the CSC proliferation and on stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSCenriched mammospheres. Finally, the efficacy of the NCS in combination with PTX was analyzed in vivo using an orthotopic mice model of MDA-MB-231 cells. Results Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The solely use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination with 8Q and NCS counteracted this pro-CSC activity of PTX whilst significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth, and limited the dissemination of the disease by reducing the circulating tumor cells and the incidence of lung metastasis. Conclusions The combination of 8Q and NCS with PTX at established ratios inhibits both, the proliferation of differentiated cancer cells and the viability of CSCs, opening a way to more efficacious TNBC treatments.

Mobilization of Peripheral Blood Stem Cells with Paclitaxel and rhG-CSF in High-Risk Breast Cancer Patients

2002 ◽  
Vol 11 (2) ◽  
pp. 415-421 ◽  
Author(s):  
Kenneth R. Meehan ◽  
Rebecca Slack ◽  
Edmund Gehan ◽  
Herbert B. Herscowitz ◽  
Ellen M. Areman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
High Risk ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Peripheral Blood Stem Cells ◽  
Blood Stem Cells ◽  
High Risk Breast Cancer ◽  
High Risk Breast ◽  
Risk Breast Cancer

scholarly journals Tumor suppressive function of Matrin 3 in the basal-like breast cancer

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Jaehyuk Yang ◽  
Seung Jun Lee ◽  
Yongseok Kwon ◽  
Li Ma ◽  
Jongchan Kim
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Patient Survival ◽  
Apoptotic Cell ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Basal Like Breast Cancer ◽  
Tumor Suppressive Function

Abstract Background Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. Methods We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. Results MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. Conclusions Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

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