scholarly journals IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1010 ◽  
Author(s):  
Damiano Cosimo Rigiracciolo ◽  
Nijiro Nohata ◽  
Rosamaria Lappano ◽  
Francesca Cirillo ◽  
Marianna Talia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Triple Negative ◽  
Cancer Genomics ◽  
Treatment Options ◽  
Signal Transduction Pathway ◽  
Growth Potential ◽  
Nuclear Accumulation

Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype that currently lacks targeted treatment options. The role played by the insulin-like growth factor-1 (IGF-1) and its cognate receptor IGF-1R in TNBC has been reported. Nevertheless, the molecular mechanisms by which the IGF-1/IGF-1R system may contribute to TNBC progression still remains to be fully understood. By computational analysis of the vast cancer genomics information in public databases (TCGA and METABRIC), we obtained evidence that high IGF-1 or IGF-1R levels correlate with a worse clinical outcome in TNBC patients. Further bioinformatics analysis revealed that both the focal adhesion and the Hippo pathways are enriched in TNBC harboring an elevated expression of IGF-1 or IGF-1R. Mechanistically, we found that in TNBC cells, the IGF-1/IGF-1R system promotes the activation of the FAK signal transduction pathway, which in turn regulates the nuclear accumulation of YAP (yes-associated protein/yes-related protein) and the expression of its target genes. At the biological level, we found that the IGF-1/IGF-1R-FAK-YAP network cascade triggers the growth potential of TNBC cells, as evaluated in different experimental systems. Overall, our results suggest that the IGF-1/IGF-1R/FAK/YAP axis may contribute to the progression of the aggressive TNBC subtype.

NFKBIA deletion in triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1012-1012 ◽  
Author(s):  
Markus Bredel ◽  
Hyunsoo Kim ◽  
Nanda K. Thudi ◽  
Denise M. Scholtens ◽  
James A. Bonner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Target Genes ◽  
Triple Negative ◽  
Lung Metastases ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Breast Cancers ◽  
Suppressor Activity ◽  
Free Survival

1012 Background: While effective, target-directed therapies are available for ER-positive and HER2-amplified breast cancer, adjuvant therapeutic options for triple-negative breast cancer (TNBC) are limited in the absence of well-defined molecular targets. Constitutive activation of oncogenic nuclear factor kB (NFkB) has been associated with ER-negative or basal-like (BL) breast cancers, but the underlying mechanism of this activation remains undefined. We previously showed that deletion of the endogenous NFkB repressor gene NFKBIA associates with EGFR non-amplified glioblastoma multiforme and portends unfavorable clinical outcome (Bredel et al. NEJM 2011). Methods: We analyzed >5,000 human breast cancers for deletions, mutations and/or expression of NFKBIA. We studied tumor suppressor activity of NFKBIA and the effect of targeted NFkB inhibition in cell culture with various NFKBIA genotypes. We compared molecular results with outcomes of affected persons. Results: NFKBIA is often (10.8%) deleted but not mutated in breast cancer. NFKBIA deletions are significantly associated with TNBC (32.8%) and particularly frequent in the BL subtype (36.7%). Loss of NFKBIA exerts a haploinsufficient effect on NFKBIA expression and the transactivation of several NF-kB target genes with important roles in breast carcinogenesis. Restoration of NFKBIA expression or pharmacologic NFkB inhibition attenuates the malignant phenotype of cells cultured from TNBC with NFKBIA deletion. Deletion and low expression of NFKBIA are highly associated with unfavorable overall survival, independent of patient age, tumor stage, nodal status, and tumor subtype. Loss of NFKBIA expression portends significantly poorer disease-specific survival, recurrence-free survival, and distant metastasis-free survival. Moreover, NFKBIA expression is significantly associated with duration of metastasis-free survival in subgroups of patients with brain or lung metastases from breast cancer. Conclusions: NFKBIA is a new, prognostically relevant, molecular target in TNBC, which remains a clinically challenging subtype of breast cancer with limited treatment options.

scholarly journals Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2372 ◽  
Author(s):  
Boopathi Subramaniyan ◽  
Sangita Sridharan ◽  
Cory M. Howard ◽  
Augustus M.C. Tilley ◽  
Tupa Basuroy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Breast Cancer Metastasis ◽  
Nuclear Accumulation ◽  
Genetic Ablation ◽  
Gsk 3Β ◽  
The Stability

The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.

scholarly journals A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/β-catenin signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wei Xie ◽  
Huijie Zhao ◽  
Fengxian Wang ◽  
Yiyun Wang ◽  
Yuan He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Molecular Mechanisms ◽  
Near Infrared ◽  
Triple Negative ◽  
Vasculogenic Mimicry ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Antitumor Effects ◽  
Mouse Xenograft Model

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, the efficacy of such treatments has been called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, the first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties of TNBC cells, resulting from the activation of Wnt/β-catenin signaling in response to hypoxia. As a critical receptor of Wnt/β-catenin signaling, Frizzled-7 (Fzd7) is aberrantly expressed in TNBC, indicating Fzd7 a potential target for developing drugs to be combined with anti-angiogenic agents. Methods Hybridoma technique and antibody humanization technique were utilized to generate a Fzd7-targeting antibody (SHH002-hu1). Biolayer interferometry (BLI) assay and near infrared (NIR) imaging were conducted to detect the affinity and targeting ability of SHH002-hu1. Next, whether SHH002-hu1 could suppress the invasion and migration of TNBC cells induced by Bevacizumab were validated, and the underlying molecular mechanisms were elucidated by luciferase reporter and western blot assays. The nude-mice transplanted TNBC models were established to assess the anti-TNBC activities of SHH002-hu1 when combined with Bevacizumab. Then, the effects on putative TNBC stem-like cells and Wnt/β-catenin signaling were evaluated by immunofluorescence (IF). Further, the tumor-initiating and self-renew capacity of TNBC cells were studied by secondary nude mouse xenograft model and sphere formation assay. In addition, the effects of SHH002-hu1 on the adaptation of TNBC cells to hypoxia were evaluated by the detection of vasculogenic mimicry (VM) and hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Results The novel humanized antibody targeting Fzd7 (SHH002-hu1) exhibited extremely high affinity with Fzd7, and specifically targeted to Fzd7+ cells and tumor tissues. SHH002-hu1 repressed invasion, migration and epithelial-mesenchymal cell transformation (EMT) of TNBC cells induced by Bevacizumab through abating Wnt/β-catenin signaling. SHH002-hu1 significantly enhanced the capacity of Bevacizumab to inhibit the growth of TNBC via reducing the subpopulation of putative TNBC stem-like cells, further attenuating Bevacizumab-enhanced tumor-initiating and self-renew capacity of TNBC cells. Moreover, SHH002-hu1 effectively restrained the adaptation of TNBC cells to hypoxia via disrupting Wnt/β-catenin signaling. Conclusion SHH002-hu1 significantly enhances the anti-TNBC capacity of Bevacizumab, and shows the potential of preventing TNBC recurrence, suggesting SHH002-hu1 a good candidate for the synergistic therapy together with Bevacizumab.

scholarly journals Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Lisa Agnello ◽  
Silvia Tortorella ◽  
Annachiara d’Argenio ◽  
Clarissa Carbone ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Tumor Targeting ◽  
Triple Negative ◽  
Ex Vivo ◽  
Treatment Options ◽  
Negative Control ◽  
Therapeutic Effects ◽  
Metastatic Setting

Abstract Background Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC. Methods Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses. Results We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs. Conclusions Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β-catenin signaling pathway

2013 ◽  
Vol 220 (3) ◽  
pp. 219-228 ◽  
Author(s):  
Hongzhong Li ◽  
Bing Yang ◽  
Jing Huang ◽  
Tingxiu Xiang ◽  
Xuedong Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Growth Potential

scholarly journals Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3357
Author(s):  
Hongmei Zheng ◽  
Sumit Siddharth ◽  
Sheetal Parida ◽  
Xinhong Wu ◽  
Dipali Sharma
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Combined Treatment ◽  
High Mobility ◽  
Sphingosine 1 Phosphate ◽  
Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

scholarly journals Triple Negative Breast Cancer: A review of common therapeutic Targets and Current Treatment options.

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Daud Akhtar ◽  
Ahsen Chaudhry
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Side Effects ◽  
Triple Negative Breast Cancer ◽  
Cancer Du Sein ◽  
Triple Negative ◽  
Treatment Options ◽  
Cell Signalling ◽  
Effets Secondaires ◽  
Breast Cancer Chemotherapy

Triple negative breast cancer (TNBC) is a subtype of breast cancer which lacks ER, PR, and HER2 expression. It is characterized by poor prognosis and resistance to standard treatment forms for breast cancer. Chemotherapy is still currently the core neo-adjuvant treatment option for patients with TNBC, although it has mixed levels of efficacy on overall survival and many serious side effects. Platinum- based therapies have been used to treat TNBC in conjunction with chemotherapy, but they are not a widely effective treatment due to the heterogeneity of TNBC. For this reason, other novel approaches, particularly those which target molecular components involved in TNBC pathogenesis, are being investigated. Angiogenesis inhibitors, which include monoclonal antibodies or small molecules that inhibit VEGF, have been shown to improve progression-free survival, but have not demonstrated an impact on overall survival. PARP enzyme inhibitors, when combined with chemotherapy and carboplatin for the treatment of TNBC, have demonstrated a significant reduction in risk progression and mortality. However, the majority of PARP inhibitors are still in trials and their effectiveness in clini- cal settings has yet to be determined. Additional proposed targets for directed therapy against TNBC include cell signalling pathways involving EGFR or PI3K. Overall, issues such as treatment resistance and side effects are important challenges that must be overcome in order to enable improvements in patient prognosis and clinical impact. RÉSUMÉ Le cancer du sein triple négatif (CSTN) est un sous-type de cancer du sein auquel il manque les récepteurs d’œstrogènes (ER), les récepteurs de progestérone (PR) et l’expression de HER2. Il est caractérisé par un pronostic défavorable et une résistance aux traite- ments standards du cancer du sein. À l’heure actuelle, la chimiothérapie est encore l’option principale de traitement néoadjuvant pour les patients ayant le CSTN, bien qu’elle ait des niveaux variés d’efficacité sur la survie globale, ainsi que de nombreux effets secondaires sérieux. Les thérapies à base de platine ont été utilisées pour traiter le CSTN en conjonction avec la chimiothérapie, mais elles ne sont pas très efficaces étant donné l’hétérogénéité du CSTN. En raison de cela, d’autres approches novatrices, particulièrement celles qui ciblent les composantes moléculaires impliquées dans la pathogenèse du CSTN, font actuellement l’objet d’enquêtes. Les inhibiteurs de l’angiogenèse, dont les anticorps monoclonaux ou les petites molécules inhibant le VEGF, ont démontré la capacité d’améliorer la survie sans progression de la maladie, mais n’ont pas démontré d’impact sur la survie globale. Les inhibiteurs d’enzymes PARP, lorsque combinés avec la chimiothérapie et le carboplatine pour le traitement du CSTN, ont démontré une réduction significative du risque de progression et de la mortalité. Toutefois, la majorité des inhibiteurs PARP subissent encore des essais et leur efficacité clinique reste à être déterminée. D’autres cibles suggérées pour la thérapie dirigée contre le CSTN incluent les voies de signalisation impliquant le EGFR ou le PI3K. Dans l’ensemble, des problèmes tels la résistance au traitement et les effets secondaires sont des défis importants qui doivent être surmontés afin de permettre des améliorations au niveau du pronostic du patient et de l’impact clinique. 

scholarly journals Opportunities for metastatic triple negative breast cancer therapy

2021 ◽  
Vol 23 (1) ◽  
pp. 78-81
Author(s):  
Inna P. Ganshina ◽  
Olga O. Gordeeva ◽  
Mariam S. Manukyan
Keyword(s):  
Breast Cancer ◽  
Russian Federation ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Treatment Results ◽  
The Russian Federation ◽  
Biological Heterogeneity ◽  
New Treatment

Metastatic triple negative breast cancer (mTNBC) is a difficult task for the chemotherapist in view of the disease aggressiveness, biological heterogeneity of the tumor, as well as the limit of therapy options. The approved modern drugs, such as immunotherapy and PARP inhibitors, have improved the treatment results in women with mTNBC. However, not all women are the candidates for this kind of therapy due to the lack of suitable points of application. In this context, high hopes are placed on the new treatment options currently being studied in clinical trials. The review summarizes data on advanced drugs that have demonstrated their efficacy in this multiplex group of women, but not yet registered at the territory of the Russian Federation Russian Federation, and will allow us to form an idea of the future algorithm of treatment of women with mTNBC.

Association of statin use with clinical outcomes in patients with triple-negative breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 523-523
Author(s):  
Malgorzata Nowakowska ◽  
Xiudong Lei ◽  
Mikayla R Thompson ◽  
Simona Flora Shaitelman ◽  
Mackenzie Wehner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Statin Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Hazard Ratio ◽  
Stage I ◽  
Cancer Outcomes ◽  
Breast Cancer Outcomes ◽  
Statin Use

523 Background: Statins have been shown to target pathways related to breast cancer carcinogenesis, specifically in more aggressive breast cancer subtypes such as triple negative breast cancer (TNBC). Given the limited toxicity profile, low cost, and ease of use of statins, an association between statin therapy and improved breast cancer outcomes, particularly in aggressive breast cancers with more limited treatment options, could have important public health implications. Here we examine the association of statin therapy with breast cancer outcomes in women with stage I-III breast cancer, specifically TNBC. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER)-Medicare and Texas Cancer Registry (TCR)-Medicare data. We included women age 66 years or older with histologically confirmed stage I-III breast cancer diagnosed from 2008-2015. We used multivariable Cox proportional hazards regression models to examine the association of statin use with overall survival (OS) and breast cancer specific survival (BCSS) adjusting for age, race, education, state buy-in, residence area, stage, subtype, endocrine therapy, radiation, chemotherapy, surgery, baseline statin use, comorbidity, and baseline hypertension. For BCSS, we accounted for the competing risk of death using the Fine and Grey method. We required all individuals to survive until 12 months post-diagnosis, which we defined as the start of the follow-up period, to account for immortal time bias. Results: We identified 45,063 patients with stage I-III breast cancer meeting inclusion criteria, out of which 22,518 (50.0%) received a statin within one year following diagnosis (statin-users). The 5-year cumulative estimates of breast cancer specific deaths were 5.9% and 6.9% for statin-users and non-users (P <.001), respectively. In the overall cohort, adjusted models showed a statistically significant association between statin use and improved BCSS (subdistribution hazard ratio [SHR], 0.82; 95% CI, 0.70 to 0.97; P =.021), but no association with OS (hazard ratio [HR], 0.96; 95% CI, 0.90 to 1.03; P =.23). The association was strongest in patients with TNBC for BCSS (SHR, 0.60; 95% CI, 0.42 to 0.86; P =.006) and OS (HR, 0.76; 95% CI, 0.61 to 0.95; P =.018). Stratification by stage showed that the effect of statin therapy in TNBC was limited to patients with localized disease. Our results were consistent using propensity score matched models and when limiting our analysis to statin therapy initiated following breast cancer diagnosis. Conclusions: Among women with non-metastatic breast cancer, we found that statin use was associated with an OS and BCSS benefit among women with TNBC. Our data suggest that statins may have a role as an adjuvant therapy in select patients with breast cancer and supports further investigation, particularly among patients with TNBC, for whom effective treatment options are more limited.

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