Polymorphic Analysis of Connexin 43 in Early as well as Advanced Stages of Breast Cancer in Kashmiri Population

Currently, the urgent task is to search for new biomarkers as a promising tool for early detection and monitoring of breast cancer. The aim of the study was to study the level of cytokines in the saliva of patients with breast cancer. In the case-control study volunteers participated, which were divided into 3 groups: the main (breast cancer, n = 43), the comparison group (fibroadenoma, n = 32) and the control group (conditionally healthy, n = 39). All participants were questioned; biochemical examination of saliva, histological verification of the diagnosis was carried out. Intergroup differences are estimated by a nonparametric criterion. It is shown that in the context of breast cancer, the level of cytokines (IL-2, IL-4, IL-6, IL-10 and IL-18) is increasing, except for IL-8, the content of which decreases compared to the control group. When the disease progresses by the nature of the dynamics, the parameters are divided into two groups: IL-2, IL-4, IL-18 and IL-6, IL-8, IL-10. For the first group of cytokines, there was a decrease in content during the transition from the early stages to the more common ones. For the second group, when passing from stages T1-2N0M0 to T1-2NjM0, the level of cytokines remains practically constant. In the future, the level of cytokines is observed for stage T3_4N0_2M0, and for IL-2, IL-4 and IL-10, the level of cytokines reaches values corresponding to early stages, whereas for IL-6, IL-8 and IL-18 in the same direction, a significant increase in indicators was noted. Additionally, the IL-6/IL-8 ratio was calculated depending on the tumor size, as well as the presence / absence of metastasis. It is shown that this ratio is statistically significantly increased in the advanced stages of the disease. Particularly interesting is the increase in this ratio in saliva at the initial stages of the disease.

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MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development

International Journal of Molecular Sciences ◽

10.3390/ijms22105214 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5214

Author(s):

Inês Figueira ◽

Joana Godinho-Pereira ◽

Sofia Galego ◽

Joana Maia ◽

János Haskó ◽

...

Keyword(s):

Breast Cancer ◽

Endothelial Cells ◽

Brain Metastases ◽

Extracellular Vesicles ◽

Triple Negative ◽

Survival Rates ◽

Brain Parenchyma ◽

Advanced Stages ◽

Breast Cancer Brain Metastases

Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.

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SDF-1α regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis

Blood ◽

10.1182/blood-2006-01-017459 ◽

2006 ◽

Vol 108 (10) ◽

pp. 3245-3252 ◽

Cited By ~ 41

Author(s):

Anabella L. Moharita ◽

Marcelo Taborga ◽

Kelly E. Corcoran ◽

Margarette Bryan ◽

Prem S. Patel ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Cancer Cells ◽

Connexin 43 ◽

Breast Cancer Cells ◽

Critical Role ◽

Contact Inhibition ◽

Enzyme Linked Immunosorbent Assay ◽

Hematopoietic Regulation

Abstract Breast cancer cells (BCCs) show preference for the bone marrow (BM). An animal model showed 2 populations of BCCs in the BM with regard to their cycling states. An in vitro model of early BC entry into BM showed normal hematopoiesis. Here, we show a critical role for BCC-derived SDF-1α in hematopoietic regulation. The studies used a coculture of BM stroma and BCCs (cell lines and stage II BCCs). Northern blots and enzyme-linked immunosorbent assay (ELISA) showed gradual decreases in SDF-1α production in BCCs as they contact BM stroma, indicating partial microenvironmental effects caused by stroma on the BCCs. SDF-1 knock-down BCCs and increased exogenous SDF-1α prevented contact inhibition between BCCs and BM stroma. Contact inhibition was restored with low SDF-1α levels. Long-term culture-initiating assays with CD34+/CD38–/Lin– showed normal hematopoiesis provided that SDF-1α levels were reduced in BCCs. Gap junctions (connexin-43 [CX-43]) were formed between BCCs and BM stroma, with concomitant interaction between CD34+/CD38–/Lin– and BM stroma but not with the neighboring BCCs. In summary, SDF-1α levels are reduced in BCCs that contact BM stroma. The low levels of SDF-1α in BCCs regulate interactions between BM stroma and hematopoietic progenitors, consequently facilitating normal hematopoiesis.

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ACE gene polymorphism in breast cancer patients of ethnic Kashmiri population

Chronicles of Young Scientists ◽

10.4103/2229-5186.76986 ◽

2010 ◽

Vol 1 (4) ◽

pp. 40 ◽

Cited By ~ 2

Author(s):

MushtaqA Siddiqi ◽

Nidda Syeed ◽

Safiya Abdullah ◽

ASyed Sameer ◽

SyedAkhtar Husain ◽

...

Keyword(s):

Breast Cancer ◽

Gene Polymorphism ◽

Cancer Patients ◽

Breast Cancer Patients ◽

Ace Gene ◽

Ace Gene Polymorphism ◽

Kashmiri Population

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CA-549 Serum Levels in Breast Cancer Monitoring

The International Journal of Biological Markers ◽

10.1177/172460089200700402 ◽

1992 ◽

Vol 7 (4) ◽

pp. 217-221 ◽

Cited By ~ 6

Author(s):

C. Zamagni ◽

A. Martoni ◽

N. Cacciari ◽

B. Bellanova ◽

F. Vecchi ◽

...

Keyword(s):

Breast Cancer ◽

Complete Remission ◽

Clinical Outcome ◽

Clinical Signs ◽

Serum Levels ◽

Objective Evaluation ◽

Breast Cancer Patients ◽

Metastatic Site ◽

Advanced Stages ◽

Extent Of Disease

CA-549 serum levels were assessed in 288 patients, 156 with early breast cancer (after surgery) and 132 with advanced breast cancer. CA-549 was abnormal (> 12 U/ml) in 25/156 patients (16%) without clinical signs of disease after surgery (median 9 U/ml), in 49/60 patients (82%) with disease in progression (P) (median 50 U/ml), in 19/27 patients (70%) with stationary disease (NC) (median 14 U/ml), in 25/33 patients (76%) with partial remission (PR) (median 18 U/ml) and in 4/12 patients (33%) with complete remission (CR) (median 9 U/ml). CA-549 serum levels correlated mainly with the extent of disease and secondarily with the prevalent metastatic site, higher values being observed in patients with visceral involvement (median 32.5 U/ml). CA-549 serum levels were also assessed in 51 patients at the start of treatment and at the time of objective evaluation: the results underline the concordance of CA-549 behavior with the clinical outcome in 71% of the cases. We conclude that CA-549 is a useful marker for monitoring breast cancer patients during the advanced stages of the disease.

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Mechanism of Regulatory Effect of MicroRNA-206 on Connexin 43 in Distant Metastasis of Breast Cancer

Chinese Medical Journal ◽

10.4103/0366-6999.176071 ◽

2016 ◽

Vol 129 (4) ◽

pp. 424-434 ◽

Cited By ~ 12

Author(s):

Zi-Jing Lin ◽

Jia Ming ◽

Lu Yang ◽

Jun-Ze Du ◽

Ning Wang ◽

...

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Connexin 43 ◽

Regulatory Effect

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Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

Cancers ◽

10.3390/cancers12102798 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2798

Author(s):

Alexander Tishchenko ◽

Daniel D. Azorín ◽

Laia Vidal-Brime ◽

María José Muñoz ◽

Pol Jiménez Arenas ◽

...

Keyword(s):

Breast Cancer ◽

Gap Junctions ◽

Small Molecules ◽

Cancer Cells ◽

Signaling Pathways ◽

Connexin 43 ◽

Breast Cancer Cell Lines ◽

Tunneling Nanotubes ◽

Cx43 Expression ◽

Cancer Signaling

Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.

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The Prognostic Value of the Expression of SMC4 mRNA in Breast Cancer

Disease Markers ◽

10.1155/2019/2183057 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Rui-min Ma ◽

Fan Yang ◽

Du-ping Huang ◽

Min Zheng ◽

Yi-luan Wang

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Mrna Level ◽

The Cancer Genome Atlas ◽

Paired Samples ◽

Cancer Genome Atlas ◽

Advanced Stages ◽

Independent Risk Factors ◽

Cancer Tissues ◽

Structural Maintenance Of Chromosomes

Aim. To investigate the mRNA expression and clinical significance of structural maintenance of chromosomes protein 4 (SMC4) in breast cancer. Methods. A total of 23 paired samples were sequenced, and data from the Cancer Genome Atlas were analyzed. Results. SMC4 mRNA level was significantly upregulated in breast cancer tissues (P<0.001). Patients with high mRNA expression of SMC4 had significantly poor survival (P=0.012). Subgroup analyses show that in nontriple negative breast cancer (non-TNBC) patients, the high SMC4 mRNA expression, older age (>65), negative progesterone receptor, and advanced stages (III-IV) were independent risk factors (HR=3.293, 95% CI 1.257-8.625, P=0.015). In patients with TNBC, high mRNA expression of SMC4 correlated with better survival rate (P<0.046). Conclusion. SMC4 mRNA level is a good prognostic biomarker for patients with breast cancer.

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Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

Oncogene ◽

10.1038/sj.onc.1205630 ◽

2002 ◽

Vol 21 (32) ◽

pp. 4992-4996 ◽

Cited By ~ 39

Author(s):

Michael V Dubina ◽

Nikolay A Iatckii ◽

Dimitrii E Popov ◽

Sergei V Vasil'ev ◽

Vladimir A Krutovskikh

Keyword(s):

Colon Cancer ◽

Connexin 43 ◽

Connexin 32 ◽

Advanced Stages ◽

Sporadic Colon Cancer

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Plasma Concentrations of Matrilysins MMP-7 and MMP-26 as Diagnostic Biomarkers in Breast Cancer

Journal of Clinical Medicine ◽

10.3390/jcm10071436 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1436

Author(s):

Barbara Maria Piskór ◽

Andrzej Przylipiak ◽

Emilia Dąbrowska ◽

Iwona Sidorkiewicz ◽

Marek Niczyporuk ◽

...

Keyword(s):

Breast Cancer ◽

Plasma Levels ◽

Proteolytic Enzymes ◽

Plasma Concentrations ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Diagnostic Utility ◽

Study Results ◽

Advanced Stages ◽

Disease Study

Metalloproteinases (MMPs) are a group of proteolytic enzymes involved in the maintenance of a proper structure of extracellular matrix (ECM). Matrilysins (MMP-7 and MMP-26) are members of the MMPs group that show promise as potential breast cancer (BC) markers. The aim of the study was to evaluate plasma levels of MMP-7, MMP-26 and CA 15-3 individually and in combination and assess the diagnostic utility of studied matrilysins in patients with BC. The study group consisted of 120 patients with BC, and the control group consisted of 40 subjects with benign breast cancer and 40 healthy women. Concentrations of MMP-7 and MMP-26 were determined by enzyme-linked immunosorbent assay, and CA 15-3 by chemiluminescent microparticle immunoassay. Plasma levels of MMP-7 were significantly higher in the BC group than in the control group. Concentrations of MMP-26 and CA 15-3 were highest in stages II and IV of the disease. The highest diagnostic sensitivity was observed in stages III and IV BC for the combination of all tested markers (92.5%). The highest diagnostic specificity was noted for all tested parameters combined in the BC group (95.0%). The area under the receiver operating characteristic (ROC) curve (AUC) for the combination of markers (MMP-7+MMP-26+CA 15-3) was the largest (0.9138) in stages III and IV. Individual marker analysis showed that MMP-7 had the highest AUC (0.8894) in advanced stages of the disease. Study results indicate that MMP-7 could be used as an additional marker that would improve the diagnostic utility of CA 15-3 in early stages of BC. Therefore, the combined assessment of MMP-7 and MMP-26 with CA 15-3 might be useful in determining disease progression. Further studies are needed to evaluate whether matrilysins show promise as potential markers for improving the diagnosis of BC.

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