scholarly journals Wnt/β-catenin inhibition disrupts drug-tolerance in isogenic carboplatin-resistant models of Triple-Negative Breast Cancer.

2021 ◽  
Author(s):  
Willy Antoni Abreu de Oliveira ◽  
Stijn Moens ◽  
Youssef El Laithy ◽  
Bernard K. van der Veer ◽  
Paraskevi Athanasouli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Tnbc Cell

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by both limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers' expression, formation of tumorspheres, and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

scholarly journals Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Willy Antoni Abreu de Oliveira ◽  
Stijn Moens ◽  
Youssef El Laithy ◽  
Bernard K. van der Veer ◽  
Paraskevi Athanasouli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Tnbc Cell

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/β-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers’ expression, formation of tumorspheres and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

Abstract 263: Identification of subgroup of triple negative breast cancer by cancer stem cell markers.

2013 ◽  
Author(s):  
Kumiko Kida ◽  
Takashi Ishikawa ◽  
Akimitsu Yamada ◽  
Kazuhiro Shimada ◽  
Kazutaka Narui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cancer Stem Cell Markers

scholarly journals Coordinated regulation of WNT/β-catenin, c-Met, and Integrin signalling pathways by miR-193b controls triple negative breast cancer metastatic traits

2021 ◽  
Author(s):  
Chiara Giacomelli ◽  
Janine Jung ◽  
Astrid Wachter ◽  
Susanne Ibing ◽  
Rainer Will ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cell Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Gene Set Enrichment Analysis ◽  
Signalling Pathways ◽  
Stem Cell Markers ◽  
Candidate Mirnas ◽  
Tnbc Cell

Background: Triple Negative Breast Cancer (TNBC) is the most aggressive subtype of Breast Cancer (BC). Treatment options for TNBC patients are limited and further insights into disease aetiology are needed to develop better therapeutic approaches. microRNAs' ability to regulate multiple targets could hold a promising discovery approach to pathways relevant for TNBC aggressiveness. Thus, we address the role of miRNAs in controlling signalling pathways and phenotypes relevant to the biology of TNBC. Methods: To identify miRNAs regulating WNT/β-catenin, c-Met, and integrin signalling pathways, we performed a high-throughput targeted proteomic approach, investigating the effect of 800 miRNAs on the expression of 62 proteins in the MDA-MB-231 TNBC cell line. We then developed a novel network analysis, Pathway Coregulatory (PC) score, to detect miRNAs regulating the three pathways. Using in vitro assays for cell growth, migration, apoptosis, and stem-cell content, we validated the function of candidate miRNAs. Bioinformatic analyses using BC patients' datasets were employed to assess expression of miRNAs as well as their pathological relevance in TNBC patients. Results: We identified six candidate miRNAs coordinately regulating the three signalling pathways. Quantifying cell growth of three TNBC cell lines upon miRNA gain-of-function experiments, we characterised miR-193b as a strong and consistent repressor of this phenotype. Importantly, the effects of miR-193b were stronger than chemical inhibition of the individual pathways. We further demonstrated that miR-193b induced apoptosis, repressed migration, and regulated stem-cell markers in MDA-MB-231 cells. Furthermore, miR-193b expression was the lowest in patients classified as TNBC or Basal compared to other subtypes when classified by PAM50 signatures. Gene Set Enrichment Analysis showed that miR-193b expression was significantly associated with reduced activity of of WNT/β-catenin and c-Met signalling pathways in TNBC patients. Conclusions: Integrating miRNA-mediated effects and protein functions on networks, we show that miRNAs predominantly act in a coordinated fashion to activate or repress signalling pathways responsible for metastatic traits in TNBC. We further demonstrate that our top candidate, miR-193b, regulates these phenotypes to an extent stronger than individual pathway inhibition, thus proving that its effect on TNBC aggressiveness is mediated by repressing multiple interconnected pathways.

scholarly journals Coordinated regulation of WNT/β-catenin, c-Met, and integrin signalling pathways by miR-193b controls triple negative breast cancer metastatic traits

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chiara Giacomelli ◽  
Janine Jung ◽  
Astrid Wachter ◽  
Susanne Ibing ◽  
Rainer Will ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cell Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Gene Set Enrichment Analysis ◽  
Signalling Pathways ◽  
Stem Cell Markers ◽  
Candidate Mirnas ◽  
Tnbc Cell

Abstract Background Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). Treatment options for TNBC patients are limited and further insights into disease aetiology are needed to develop better therapeutic approaches. microRNAs’ ability to regulate multiple targets could hold a promising discovery approach to pathways relevant for TNBC aggressiveness. Thus, we address the role of miRNAs in controlling three signalling pathways relevant to the biology of TNBC, and their downstream phenotypes. Methods To identify miRNAs regulating WNT/β-catenin, c-Met, and integrin signalling pathways, we performed a high-throughput targeted proteomic approach, investigating the effect of 800 miRNAs on the expression of 62 proteins in the MDA-MB-231 TNBC cell line. We then developed a novel network analysis, Pathway Coregulatory (PC) score, to detect miRNAs regulating these three pathways. Using in vitro assays for cell growth, migration, apoptosis, and stem-cell content, we validated the function of candidate miRNAs. Bioinformatic analyses using BC patients’ datasets were employed to assess expression of miRNAs as well as their pathological relevance in TNBC patients. Results We identified six candidate miRNAs coordinately regulating the three signalling pathways. Quantifying cell growth of three TNBC cell lines upon miRNA gain-of-function experiments, we characterised miR-193b as a strong and consistent repressor of proliferation. Importantly, the effects of miR-193b were stronger than chemical inhibition of the individual pathways. We further demonstrated that miR-193b induced apoptosis, repressed migration, and regulated stem-cell markers in MDA-MB-231 cells. Furthermore, miR-193b expression was the lowest in patients classified as TNBC or Basal compared to other subtypes. Gene Set Enrichment Analysis showed that miR-193b expression was significantly associated with reduced activity of WNT/β-catenin and c-Met signalling pathways in TNBC patients. Conclusions Integrating miRNA-mediated effects and protein functions on networks, we show that miRNAs predominantly act in a coordinated fashion to activate or repress connected signalling pathways responsible for metastatic traits in TNBC. We further demonstrate that our top candidate, miR-193b, regulates these phenotypes to an extent stronger than individual pathway inhibition, thus emphasizing that its effect on TNBC aggressiveness is mediated by the coordinated repression of these functionally interconnected pathways.

scholarly journals Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3871
Author(s):  
Emma Rodriguez ◽  
Guangsheng Pei ◽  
Sang T. Kim ◽  
Alexis German ◽  
Prema Robinson
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Cell Line ◽  
Pc12 Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Neuronal Cell ◽  
Receptor Antagonism ◽  
Tnbc Cell

Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC.

scholarly journals Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pradip Shahi Thakuri ◽  
Megha Gupta ◽  
Sunil Singh ◽  
Ramila Joshi ◽  
Eric Glasgow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Protein Kinases ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Tnbc Cell

Abstract Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

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