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Signal Transduction and Targeted Therapy May 2020Although targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high...
Although targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high heterogeneity of these cancers. Mammaglobin-A (Mam-A), which is overexpressed in most breast carcinomas, has been proposed as a promising target. However, the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational study. Here, seven potential epitopes of Mam-A were disclosed, and a unique epitope was then identified in most types of breast cancers, despite the genotypic heterogeneity. With phage display technology, the epitope was determined to be N-terminal amino acids 42-51 of Mam-A (N). Then, the N epitope-specific monoclonal antibody, mAb785, was conjugated to poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with therapeutic agents, thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast cancers. The computer simulation of the N epitope and the mAb785 structures, as well as their interactions, further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Breast Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Epitopes; Female; Humans; Mammaglobin A; Nanoparticles; Neoplasm Proteins; T-Lymphocytes, Cytotoxic
PubMed: 32467564
DOI: 10.1038/s41392-020-0183-1 -
Oncology Letters Dec 2019Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and...
Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP-1 cells, an apparent proficient antigen that presents a human monocyte-like cell line, and their eventual activation of MamA2.1 (HLA-A2 immunodominant epitope of Mam-A) specific cytotoxic CD8 T lymphocytes (CTLs). The results revealed that, following treatment with methylselenol producing compounds [methylselenic acid (MSA) and dimethylselenide (DMDSe)], the expression of HLA class-I was increased and components involved with the antigen presentation machinery of THP-1 cells were upregulated. Furthermore, CTLs activated by MamA2.1 peptide presenting THP-1 cells, pre-treated with MSA and DMDSe, demonstrated an enhanced cytotoxicity in HLA-A2/Mam-A AU565 and UACC-812 breast cancer cell lines when compared with CTLs activated by THP-1 cells without drug treatment. However, no significant cytotoxicity was observed under similar conditions in HLA-A2/Mam-A MCF-7 and MDA-MB-231 breast cancer cell lines. The results indicated that treatment with methylselenol producing compounds retained antigen-dependent activation of CD8 T cells. The data of the current study demonstrated that MSA and DMDSe potentiated effector cytotoxic responses following TAA specific activation of CTLs, indicating their future role as vaccine adjuvants in cancer immunotherapy.
PubMed: 31807192
DOI: 10.3892/ol.2019.11010 -
Breast Cancer : Basic and Clinical... 2019This study determines the co-expression of mammaglobin-A, vascular endothelial growth factor receptor-3 (VEGFR3) and Ki67 by immunohistochemistry (IHC) in tissue samples...
BACKGROUND/METHODS
This study determines the co-expression of mammaglobin-A, vascular endothelial growth factor receptor-3 (VEGFR3) and Ki67 by immunohistochemistry (IHC) in tissue samples from 80 patients undergoing breast surgery (cancer or benign disease). The tissue expression was compared with the tumour histopathology and Kaplan Meier 5-year survival analysis was performed.
RESULTS
Positive breast tissue expression was observed in 53% samples for mammaglobin, 41% Ki67 and 65% VEGFR3 with a significant positive correlation between Ki67 and VEGFR3 co-expression. Ki67 and VEGFR3 expression correlated with the breast tumour grade and Ki67 expression also correlated with oestrogen receptor (ER) status. At 5 years post-operatively, 6/80 patients had died and 3 patients were alive but had cancer recurrence. High Ki67 expression significantly correlated with poor survival (disease-free and overall).
CONCLUSIONS
In this study, VEGFR3 and Ki67 expression but not mammaglobin-A correlated with breast tumour pathology. Positive Ki67 expression was also associated with a poor 5-year survival outcome.
PubMed: 31263371
DOI: 10.1177/1178223419858957 -
3 Biotech Jul 2019In the present study, the simultaneous application of gene of and - antigen on the induction of immune responses against breast cancer tumors was investigated in...
In the present study, the simultaneous application of gene of and - antigen on the induction of immune responses against breast cancer tumors was investigated in BALB/c mice. The pBudCE4.1-azurin-MAM-A recombinant vector was generated and prepared at a large scale. This recombinant vector alone or combined with chitosan nanoparticles was infused into the hip muscle of animals. Animals were divided into the "prevention" and "therapy" categories. The animals of prevention category were first, immunized by a recombinant vector and then exposed to chemical cancer inducers; while the animals in the therapy category were first treated with chemical compounds and then infused by a recombinant plasmid. The tumor tissues, infusion sites, and blood specimens were collected and examined by serological, molecular, and histological tests. The breast tumor incidence in the infused animals by recombinant plasmid alone or combined with nanoparticles (in both prevention and therapy categories) compared with infused mice by empty pBudCE4.1 vector was significantly decreased (< 0.05). These results were supported by histological studies using H&E staining. The ELISA and q-real-time PCR techniques showed the range of IFN-γ, IL-12, IL-4, and IL-17A cytokines in the infused mice by recombinant vector alone or combined with nanoparticles compared to the healthy mice and infused animals by intact pBudCE4.1 were significantly increased (< 0.05). Accordingly, the expression of the tumor markers , , and were significantly decreased in treated mice either by the sole recombinant vector or combined with nanoparticles (< 0.05). These findings indicated that pBudCE4.1-azurin-MAM-A recombinant vector plays an essential role against the formation and expansion of breast tumors in the animal model. In addition, this recombinant vector is safe and has the proper ability to stimulate the immune system. In addition, the chitosan nanoparticle represents a promising adjuvant for DNA vaccine delivery, which improves the immune system stimulation and boosts the vaccine performance.
PubMed: 31245235
DOI: 10.1007/s13205-019-1804-7 -
Acta Otorhinolaryngologica Italica :... Jun 2019
Topics: Adolescent; Adult; Aged; Aquaporin 5; Caveolin 1; Chronic Disease; Cyclooxygenase 2; Cytokines; Epithelial Cells; Gene Expression; Gene Expression Profiling; Humans; Lactoferrin; Mammaglobin A; Middle Aged; Mucin 5AC; Nasal Polyps; Retrospective Studies; Rhinitis; Sinusitis; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Young Adult
PubMed: 31131836
DOI: 10.14639/0392-100X-2361 -
PloS One 2019This meta-analysis presents evidence regarding the diagnostic accuracy of mammaglobin detected using the RT-PCR technique, related to the presence of sentinel node... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This meta-analysis presents evidence regarding the diagnostic accuracy of mammaglobin detected using the RT-PCR technique, related to the presence of sentinel node metastasis in breast cancer patients.
METHODS
The following databases were consulted: Cochrane, Lilacs, Scielo, Hinary, PubMed, Elsevier, Embase, ProQuest, the Universidad del Rosario´s Centro de Recursos Para el Aprendizaje y la Investigación (CRAI-UR) [Resource Center for Learning and Research], and the Google Scholar search engine. The quality of the studies was assessed using the QUADAS-2 and CASpe tools. The selected studies presented the necessary data to calculate diagnostic validity index of mammaglobin detection using RT-PCR, compared with the reference standard test. Global values for the sensitivity, specificity, positive predictive value, negative predictive value, probability ratios, diagnostic ORs, and summary ROC curves of this meta-analysis were obtained using the Meta-DiSc 1.4 program.
RESULTS
Initially, 731 articles were obtained; but only 25 were included in the meta-analysis. Sensitivity was 84% (95% CI: 83% - 86%), and specificity was 92% (95% CI: 91% - 93%). Positive and negative predictive values were 9.26 (95% CI: 6.47-13.26) and 0.17 (95% CI: 0.13-0.23), respectively. The diagnostic OR was 66.34 (95% CI: 42.52-103.52). The predictive area under the sROC curve was 94.78 (Q = 0.8876).
CONCLUSIONS
The evaluated diagnostic index showed that the expression of the mammaglobin biomarker has diagnostic prediction for detecting lymph node metastasis in breast cancer patients, when analyzed using RT-PCR, although more than 50% heterogeneity was found.
Topics: Biomarkers, Tumor; Breast Neoplasms; Cluster Analysis; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Mammaglobin A; Observational Studies as Topic; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; ROC Curve; Reproducibility of Results; Sensitivity and Specificity
PubMed: 31120936
DOI: 10.1371/journal.pone.0216989 -
Cancers May 2019Mammaglobin-A (MamA) is overexpressed in 40-80% of all human breast cancers. Recent phase I clinical trials of the MamA DNA vaccine showed encouraging safety outcomes....
Oligodeoxynucleotides ODN 2006 and M362 Exert Potent Adjuvant Effect through TLR-9/-6 Synergy to Exaggerate Mammaglobin-A Peptide Specific Cytotoxic CD8+T Lymphocyte Responses against Breast Cancer Cells.
Mammaglobin-A (MamA) is overexpressed in 40-80% of all human breast cancers. Recent phase I clinical trials of the MamA DNA vaccine showed encouraging safety outcomes. However, this vaccine elicited only a modest increase in MamA specific CD8+T lymphocyte (CTL) activation. As vaccine adjuvants play a critical role in enhancing the immunotherapeutic efficiency of vaccines, we tested the potential role of three synthetic CpG oligodeoxynucleotides (ODN2216-class A ODN, ODN2006-class B ODN, and ODN M362-class C ODN) to further enhance MamA specific CTL responses. Towards this, naïve CD8+T cells were obtained from healthy HLA-A2+ human donors. The HLA-A2 specific immunodominant epitope of MamA, MamA2.1 (LIYDSSLCDL), was utilized to activate naïve CD8+T cells. The THP-1 (HLA-A2+) cells were used as antigen presenting cells to stimulate naïve CD8+T cells along with (or without) co-treatment of various ODNs mentioned above. Activation of naïve CD8+T cells with the MamA2.1 peptide along with ODNs demonstrated enhanced MamA specific CTL mediated cytotoxicity on AU565 (HLA-A/MamA) breast cancer cells following co-treatment with ODN2006 and M362 compared to ODN2216 or MamA2.1 peptide alone. However, no significant cytotoxicity was noted upon treatment of MamA2.1 activated CTLs on MCF7 (HLA-A/MamA) cells, suggesting that the activation of CTLs is specific to the MamA antigen. Functional characterization studies demonstrated specific IL-12 mediated cross-talk between TLR-6 and -9 in THP-1 cells following stimulation with ODN2006 and M362, which was critical for the final cytotoxic activation of CD8+T lymphocytes. Based on these data, we conclude that ODN2006 and ODN M362 exerted a strong adjuvant effect through induction of the initial innate immune response through TLR9 upregulation followed by enhanced MamA specific CTL dependent adaptive immune responses. Our current data provide evidence for the application of Class-B/-C-CpG-ODNs as potential vaccine adjuvants towards enhancing the success of MamA based breast cancer vaccination.
PubMed: 31091800
DOI: 10.3390/cancers11050672 -
BMC Veterinary Research Jun 2018Mammaglobin, a member of secretoglobin family has been recognized as a breast cancer associated protein. Though the exact function of the protein is not fully known, its...
BACKGROUND
Mammaglobin, a member of secretoglobin family has been recognized as a breast cancer associated protein. Though the exact function of the protein is not fully known, its expression has been reported to be upregulated in human breast cancer.We focused on studying the expression of mammaglobin-B gene and protein in canine mammary tumor (CMT) tissue. Expression of mammaglobin-B mRNA and protein were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC), respectively.
RESULTS
High levels of mammaglobin-B mRNA expression (6.663 ± 0.841times) was observed in CMT as compared to age and breed matched healthy controls. Further, expression of mammaglobin-B protein was detected in paraffin-embedded mammary tumor tissues from the same subjects by IHC. Mammaglobin-B protein was overexpressed only in 6.67% of healthy mammary glands while, a high level of its expression was scored in 76.7% of the CMT subjects. Moreover, no significant differences in terms of IHC score and qRT-PCR score with respect to CMT histotypes or tumor grades were observed, indicating that mammaglobin-B over-expression occurred irrespective of CMT types or grades.
CONCLUSION
Overall, significantly increased expression of mammaglobin-B protein was found in CMTs with respect to healthy mammary glands, which positively correlates to its transcript. These findings suggest that overexpression of mammaglobin-B is associated with tumors of canine mammary glands.
Topics: Animals; Dog Diseases; Dogs; Female; Gene Expression; Immunohistochemistry; Mammaglobin B; Mammary Neoplasms, Animal; Neoplasm Grading; RNA, Messenger; RNA, Neoplasm; Real-Time Polymerase Chain Reaction
PubMed: 29903015
DOI: 10.1186/s12917-018-1507-z -
OncoTargets and Therapy 2018Mammaglobin A expression in peripheral blood (PB) of breast carcinoma patients has been evaluated by various studies, but the findings have been inconsistent. This... (Review)
Review
Mammaglobin A expression in peripheral blood (PB) of breast carcinoma patients has been evaluated by various studies, but the findings have been inconsistent. This meta-analysis aimed to clarify the prognostic value of mammaglobin A in the PB of breast carcinoma patients and define its relationships with clinicopathological features. PubMed, EMBASE, and the Cochrane Library databases were systematically searched for eligible studies through September 26, 2017. A total of 20 studies involving 2,323 patients were analyzed, and the data were independently extracted by two researchers. The combined hazard ratios (HRs) with 95% CI was used to assess the association between survival data and plasma mammaglobin A expression, and odds ratios (ORs) and 95% CIs were used to assess the associations between clinicopathological parameters and plasma mammaglobin A expression. The results indicated that plasma mammaglobin A expression was a predictor of poor prognosis for breast carcinoma patients, with an HR of 2.08 (95% CI=1.48-2.91; <0.0001) for overall survival. Moreover, plasma mammaglobin A was significantly associated with lymph node metastasis (OR=2.00; 95% CI=1.17-3.45; =0.01) and advanced tumor stage (OR=3.01; 95% CI=1.57-5.77; =0.0009) in breast carcinoma patients. However, the results revealed that plasma mammaglobin A was not significantly associated with tumor size (OR=1.29; 95% CI=0.46-3.66; =0.63), tumor differentiation (OR=0.99; 95% CI=0.63-1.57; =0.97), menopausal status (OR=0.75; 95% CI=0.48-1.18; =0.22), estrogen receptor status (OR=0.78; 95% CI=0.44-1.36; =0.38), progesterone receptor status (OR=0.76; 95% CI=0.57-1.02; =0.07), or human epidermal growth factor receptor 2 status (OR=1.12; 95% CI=0.78-1.59; =0.54). In conclusion, the results demonstrate that positive plasma mammaglobin A expression might serve as a biomarker of poor prognosis for breast carcinoma patients.
PubMed: 29881297
DOI: 10.2147/OTT.S156556 -
Turk Patoloji Dergisi 2018Cytomorphologic differentiation of metastatic breast carcinoma from non breast metastases in cytological materials can be difficult. Current breast immunocytochemical... (Comparative Study)
Comparative Study
Can GATA3 Immunocytochemistry be Utilized as a Reliable Diagnostic Marker for Metastatic Breast Carcinoma in Cytological Materials? A Comparative Study with Mammaglobin and GCDFP-15 Expression.
OBJECTIVE
Cytomorphologic differentiation of metastatic breast carcinoma from non breast metastases in cytological materials can be difficult. Current breast immunocytochemical markers have low sensitivities. Transcription factor GATA 3 is a promising marker for detecting breast differentiation in cytological materials. The aim of the study was to assess the diagnostic value of GATA 3 as a breast differentiation marker in metastatic cytological materials and to compare it with expression of mammaglobin and gross cystic disease fluid protein-15 (GCDFP-15).
MATERIAL AND METHOD
We retrospectively retrieved 133 cases of metastatic breast carcinoma from the archive the of Cytology Unit between December 2013 and June 2015. They included 77 fine needle aspiration and 56 serous effusion samples. Forty-five cytological materials from non mammary metastatic tumors were used as a control. Immunostaining was performed on cell blocks for the presence of GATA 3, mammaglobin and GCDFP-15.
RESULTS
GATA 3 nuclear staining was detected in 82.7% of metastatic breast carcinomas, and 11.1% of metastatic non mammary adenocarcinomas (p < 0.001). GATA 3 sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.7%, 88.9%, 95.7%, 63.5% and 84.3%, respectively. Mammaglobin and GCDFP-15 staining of metastatic breast carcinoma cases was positive in 70.7% and 47.1%, respectively. GATA 3 staining was significantly higher compared with mammaglobin and GCDFP-15 (p < 0.001).
CONCLUSION
GATA 3 is more sensitive marker than mammaglobin and GCDFP-15 for diagnosing metastatic breast carcinoma in cytological cell block materials. Adding mammaglobin to GATA 3 resulted in improvement in its sensitivity. GATA 3 was occasionally positive in some metastatic non mammary carcinoma that may cause misdiagnosis.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carrier Proteins; Female; GATA3 Transcription Factor; Glycoproteins; Humans; Mammaglobin A; Membrane Transport Proteins; Middle Aged; Retrospective Studies; Sensitivity and Specificity
PubMed: 29235613
DOI: 10.5146/tjpath.2017.01419