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Cancer cells can aberrantly express various markers, including transferrin receptor 1 (CD71) and β 1-integrin molecules. Their role in invasion, migration and metastasis has been demonstrated. Determination of their expression in breast cancer (BC) may be an important point to characterize the clinical course of the tumor and prognosis of the disease., Objective: To study of transferrin receptor 1 (CD71) expression by primary breast cancer cells in correlation with tumor cell phenotype., Material and Methods: Determination of BC phenotype: immunohistochemical staining method (immunofluorescence). Antibodies to ER (estrogen receptors), KL-1 (pancytokeratin), CD71 (transferrin receptor), CD29 ( β 1-integrins). CD45, CD3, CD4, CD8, CD20 infiltration was also evaluated. ZEISS microscope (AXIOSKOP; Germany), method of G.J. Hammerling et al. Statistical processing: IBM-SPSS Statistics v.21., Results: 63% of BC cases had CD71+ phenotype. CD71-mosaic tumors were observed in 14.4%. β 1-integrin expression was monomorphic in 51.6% of cases and mosaic in 38.7%. 85% of ER-positive tumors were CD71-positive with a monomorphic type of reaction; p =0.014. Among ER-negative tumors, CD71-negative reactions were 2-fold more frequent and the monomorphic type was less frequent. ER-positive tumors were CD29-positive in 73%; p =0.031. 45.5% of ER+ tumors were CD29-monomorphic. Among ER-negative tumors, the frequency of CD29-monomorphic tumors was 55%. Significant infiltration by CD3+ cells was predominant in CD71-positive tumors; p =0.016. In the CD29-monomorphic phenotype, CD45+ infiltration was 31.3%, and in the mosaic phenotype, 67.1%., Conclusion: BC aberrantly expresses transferrin receptors, β 1-integrins. CD71 expression is associated with ER expression. ER-positive tumors are often monomorphic for CD71. Prominent CD3+ infiltration was present in CD71+ tumors. Expression of β 1-integrins correlated with ER+ status and weak immune infiltration.

The report of the biopsy diagnosis of the granular cell tumor with rare localization in the breast is given. Currently, the tumor is considered a neoplasm of neuroectodermal origin. Differential diagnostic criteria for the tumor are positive expression in cytoplasm of protein S-100, absence of expression of epithelial antigens, histiocytic antigens, oncoproteins, estrogens and progesterone receptors, PAS-positive reaction of intracellular granules. With ultrasound examination and mammography, a tumor always initially assessed as cancer or calcification.

Breast cancer is the most common type of cancer among women. The study of the mechanisms of metastasis, the main cause of death from breast cancer, as well as the search for new markers for early diagnosis and prognosis of breast cancer, is an extremely topical issue. New perspectives in the diagnosis and treatment of breast cancer are opened by the mechanisms of gene regulation involving non-coding RNAs, in particular, long non-coding RNAs (lncRNAs). In this work, we analyzed the methylation levels of seven lncRNA genes (MEG3, SEMA3B-AS1, HAND2-AS1, KCNK15-AS1, ZNF667-AS1, MAGI2-AS3, and PLUT) by quantitative methyl-specific PCR on a set of 79 paired (tumor/normal) samples of breast cancer. Hypermethylation of all seven lncRNA genes was revealed, and hypermethylation of HAND2-AS1, KCNK15-AS1, MAGI2-AS3, and PLUT was detected in breast cancer for the first time. It was found that the level of meth ylation of the studied lncRNA genes correlated statistically significantly with the stage of the tumor process, the size of the tumor, and the presence of metastases in the lymph nodes. Thus, methylation of the seven studied lncRNA genes is associated with the development and progression of breast cancer, and these genes can be useful as potential markers in the diagnosis and prognosis of breast cancer.

Objective: To study of the expression of epithelial-mesenchymal transition markers in various molecular subtypes of cancer and in benign breast diseases with different risks of malignant transformation., Material and Methods: An immunohistochemical study of the expression of E-cadherin, collagen II, integrin 1β, cyclin D1 was carried out in breast tissue samples: 58 with invasive breast carcinoma of no special type and 17 with benign breast diseases with a high and low risk of malignant transformation., Results: Patients with a triple negative molecular subtype are characterized by lower expression of collagen II compared with individuals with luminal A and B+ subtypes. A distinctive feature of patients with the HER2+ subtype was increased expression of cyclin D1 compared with the luminal A subtype, and in patients with the luminal B+ subtype, the expression of integrin 1β is higher than in the luminal B- and HER2+ subtypes. The expression of cyclin D1 in patients of both groups with benign diseases was lower than in all groups with invasive carcinoma, but at the same time, in patients with a low risk of malignant transformation, the expression of cyclin D1 was higher than in those with an increased risk., Conclusion: The study revealed the relationship between the expression of markers and molecular subtypes of breast tumors, in addition, some patients with benign diseases were found who need further more careful monitoring and may be at risk for the development of malignancy.

Changes in metabolic pathways are often associated with the development of a wide range of pathologies. Increased glycolysis under conditions of sufficient tissue oxygen supply and its dissociation from the Krebs cycle, known as aerobic glycolysis or the Warburg effect, is a hallmark of many malignant neoplasms. Identification of specific metabolic shifts can characterize the metabolic programming of individual types of tumor cells, the stage of their transformation, and predict their metastatic potential. Viral infection can also alter the metabolism of cells to support the process of viral replication. Infection with human immunodeficiency virus type 1 (HIV-1) is associated with an increased incidence of various cancers, and for some viral proteins a direct oncogenic effect was demonstrated. In particular, we showed that the expression of HIV-1 reverse transcriptase (RT) in 4T1 breast adenocarcinoma cells increases the tumorigenic and metastatic potential of cells in vitro and in vivo by a mechanism associated with the ability of RT to induce reactive oxygen species in cells (ROS). The aim of this work was to study the molecular mechanism of this process, namely the effect of HIV-1 RT on the key metabolic pathways associated with tumor progression: glycolysis and mitochondrial respiration. Expression of HIV-1 RT had no effect on the glycolysis process. At the same time, it led to an increase in mitochondrial respiration and the level of ATP synthesis in the cell, while not affecting the availability of the substrates, carbon donors for the Krebs cycle, which excludes the effect of RT on the metabolic enzymes of cells. Increased mitochondrial respiration was associated with restoration of the mitochondrial network despite the RT-induced reduction in mitochondrial mass. Increased mitochondrial respiration may increase cell motility, which explains their increased tumorigenicity and metastatic potential. These data are important for understanding the pathogenesis of HIV-1 infection, including the stimulation of the formation and spread of HIV-1 associated malignancies.

Research of cancer progression mechanisms and their impact on metabolism of tumor cells and tumor microenvironment cells is an important element in drug development for cancer target therapy. In this study, changes in tumor tissue and margin tissue lipid profiles, were associated with the following clinical and morphological characteristics: tumor size, cancer stage, multifocalite, tumor grade, number of lymph node metastasis, Nottingham prognostic index, total malignancy score, level of Ki67 protein. Lipid profiling was performed by reverse-phase chromato-mass spectrometry analysis of lipid tissue extract with lipid identification by characteristic fragments. In the lipid profile of tumor tissue 13 characteristic lipids were selected. Their levels significantly correlated with at least 5 clinical and morphological features. Eight of 13 belonged to phosphatidylcholines. In lipid profile of tumor microenviroment tissue 13 lipid features were selected. Their levels significantly correlated with at least 5 clinical and morphological features. Four of 13 belonged to oxidized lipids, 4 lipid features belonged to sphingomyelins, four of 13 belonged to phosphatidylethanolamines. The tumor microenvironment tissue lipid profile correlated with tumor size, cancer stage, tumor grade, number of axillary metastases, Nottingham prognostic index. The tumor tissue lipid profile correlated with tumor size, tumor grade, total malignant score, and number of axillary metastases.

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

Aim: To study the expression of the anti-apoptotic survivin protein, as well as the expression of the BIRC5 gene of its encoding primary breast carcinoma as a potential procnostic and predictive marker., Material and Methods: With the help of immunohistochemistry (IHC), as well as polymerase chain reaction in real time (real-time PCR), 67 samples (biopsy) of the primary breast carcinoma were studied for the presence of expression of the survivin protein and the gene of its encoding BIRC5., Results: Expression of survivin was determined in 47 mammary carcinoma samples, which was 70.15%. Expression of survivin was most often determined in medium and high grade ductal carcinoma (G2-G3), and was associated with lymphovenous stromal invasion (LVSI+). Expression of the survivin protein correlated with the expression of HER2-neu. In 59.6% of cases, survivin was expressed in tumors with a low Ki-67 index. Most often, survivin was expressed with luminal A and luminal B molecular-biological tumor subtype. Real-time PCR determined the expression of the BIRC5 gene in all 67 carcinoma samples. The level of normalized expression of the BIRC5 gene significantly moderately correlated with the expression of the own product of the survivin protein (r=0.704; p<0.01) and slightly correlated with the expression of the oncoprotein HER2-neu (r= -0.285; p<0.05)., Conclusion: Expression of the protein of survivin and its gene BIRC5, can be considered as an unfavorable prognostic factor and used as a predictive and prognostic marker.

Objective: To investigate the expression of PD-L1 in triple-negative and luminal B, HER2-negative breast carcinoma and to assess the association of the tumor PD-L1 status with the prognosis of the disease., Subject and Methods: The PD-L1-status of primary tumor was studied in 72 patients with breast cancer, by using an immunohistochemical method., Results: Differences were found in the incidence of carcinomas with PD-L1 expression in tumor cells depending on the molecular genetic type: there was a positive PD-L1 status in luminal B, HER2-negative tumors in 4 (14.81%) of 27 cases and in triple-negative tumors in 17 (37.78%) of 45 cases. An analysis of tumors after neoadjuvant therapy revealed a positive PD-L1-status in tumor cells in 1 of 18 patients with a moderate residual tumor load and in 6 of 13 with a high residual tumor load (5.56 and 46.15%, respectively), as estimated by the RCB system., Conclusion: The positive PD-L1 status in triple-negative breast cancer was determined more than 2 times as frequently as in luminal B, HER2-negative breast cancer (37.78 and 14.81%). There was a considerable correlation between the high residual tumor load and the positive tumor PD-L1 status.

Breast cancer (BC) is a heterogeneous tumor, the biological characteristics of which vary with its growth and progression. Information on key tumor receptors (ER, PR, HER2, and Ki-67) is the basis for individualizing the diagnostic and treatment algorithm at all BC stages; however, the feasibility of biopsy of distant metastases and the re-testing of the biological subtype of BC in its suspected progression are being actively discussed in clinical practice. This review presents an update on the features of metastasis in different biological BC subtypes and assesses the clinical and prognostic role of biopsy of distant metastases in the lung, bones, liver, and brain. It shows the frequency of discordance in receptor status between primary and recurrent tumors at different sites of metastases, as well as the impact of changes in receptor status on survival rates in different biological BC subtypes. The relevance of performing biopsies in BC progression is shown to be beyond question, because it makes it possible to confirm the fact that the disease progresses, to re-test the biological subtype of recurrent BC, and to find new targets that allow the most effective drug treatment regimens to be used.

Breast cancer is one of the most common cancers in women worldwide. Tamoxifen (TAM) provided a successful treatment for ER-positive (ER+) breast cancer for many years. However, ER+ patients with metastatic diseases respond poorly to TAM therapy and many initial responders eventually relapse. Emerging evidence indicates that long non-coding RNAs (lncRNAs) may have a critical role in the regulation of cellular processes such as cancer progression and metastasis, though the function of lncRNAs in TAM-resistance is still unclear. To investigate the role of CCAT2 in the development of resistance to TAM treatment of breast cancer, we established TAM-resistant models in MCF-7 and T47D cells. The present study demonstrates that TAM-resistant cells show a higher level of CCAT2 expression compared with TAM-sensitive cells. Biologically, CCAT2 knockdown could inhibit proliferation and induce apoptosis in TAM-resistant cells exposed to TAM. Furthermore, knockdown of CCAT2 improves the sensitivity to TAM in TAM-resistant cells. Overall, the study results provide a novel therapeutic approach for TAM-resistant patients through depleting CCAT2 expression.

The aim of this study was to establish the role of redox modification of proteins and redox status in the realization of apoptosis of MCF-7 breast adenocarcinoma cells du-ing cultivation with the SH-group blocker N-ethylmaleimide (NEM) and the SH-group protector 1,4-dithioerythritol (DTE). The activation of apoptosis in MCF-7 breast adenocarcinoma cells was shown to be due to the irreversible modification of redox sensitive protein molecules. The presence of DTE in the culture medium of cancer.cells caused reversible glutathionylation of protein molecules and did not change the: number of apoptotic MCF-7 cells.

MicroRNAs play an important role in the regulation of expression of many genes involved in cancer pathogenesis. One of the causes of miRNA level deregulation in tumors is the methylation of CpG islands in the promoter regions of the genes that encode them. Hypermethylation may lead to the suppression of miRNA gene expression and, as a consequence, to a decrease in their inhibitory effect on target gene mRNAs. A search for new miRNA genes hypermethylated in breast cancer has been carried out in the present study. The methylation of five miRNA genes associated with breast cancer (miR-132, miR-1258, miR-107, miR-130b, miR-137) has been as studied using a representative set of 41 breast cancer samples by methylation-specific PCR. Three new genes, MIR-132, MIR-137 and MIR-1258, with a high frequency of hypermethylation (41, 37 and 34%, respectively) have been identified in breast cancer. The methylation of these genes in the breast tissues of ten donors without cancer pathology in anamnesis was only found in single cases. These results enable the involvement of three miRNAs (miR-132, miR-137, miR-1258) and the methylation of the genes that encode them in the pathogenesis of breast cancer to be suggested.

Currently, no molecular biological markers do exist for early diagnosis of breast cancer. One of the possible candidates for the marker of early breast cancer is mammaglobin (MGB1) or SCGB2A2 (secretoglobin, family 2A, member 2), characterized by the maximal expression level in early breast cancer. Using the RT-PCR method MGB1 mRNA expression was examined in 57 tumor tissue samples and 57 samples of morphologically non-malignant tissue (MNT) of breast cancer (BC) patients. Specificity and sensitivity of the MGB1 mRNA assay in peripheral blood of BC patients was evaluated by nested PCR. 169 blood samples (from 95 BC patients, 22 from patients with benign breast tumors, 28 from patients with tumors of other localizations, and 24 samples from healthy donors) have been analyzed. MGB1 expression was significantly higher in BC tissue samples compared to MNT (p=0.0019). The maximal expression level was in the samples T1 (p=0.013), stage I BC (p=0.037), GI (p=0.0019). The MGB1 expression positively correlated with expression of estrogen (p = 0,034) and progesterone (p=0.0004) receptors. Sensitivity and specificity of the MGB1 mRNA assay in peripheral blood were 60.6% and 92.3%, respectively. Expression of MGB1 was higher in BC than MNT and it decreased during BC progression. The sensitivity and specificity of the MGB1 mRNA assay may be used as an additional diagnostic method.

A method of selection of DNA aptamers to breast tumor tissue based on the use of postoperative material has been developed. Breast cancer tissues were used as the positive target; the negative targets included benign tumor tissue, adjacent healthy tissues, breast tissues from mastopathy patients, and also tissues of other types of malignant tumors. During selection a pool of DNA aptamers demonstrating selective binding to breast cancer cells and tissues and insignificant binding to breast benign tissues has been obtained. These DNA aptamers can be used for identification of protein markers, breast cancer diagnostics, and targeted delivery of anticancer drugs.

Large-scale epidemiological and clinical studies have demonstrated the efficacy of metformin in oncology practice. However, the mechanisms of implementation of the anti-tumor effect of this drug there is still need understanding. In this study we have investigated the effect of metformin on the activity of adenosine deaminase and respectively adenosinergic immunosuppression in tumors and their microenvironment. The material of the study was taken during surgery of breast cacer patients receiveing metformin, and also patients which did not take this drug. The adenosine deaminase activity and substrate (adenosine) and products (inosine, hypoxanthine) concentrations were determined by HPLC. Results of this study suggest that metformin significantly alters catabolism of purine nucleotides in the node breast adenocarcinoma tisue. However, the metformin-induced increase in the adenosine deaminase activity is not sufficient to reduce the level of adenosine in cancer tissue. Thus, in metformin treated patients the adenosine concentration remained unchanged, and inosine and hypoxanthine concentration significantly increased.

In MCF-7/Dox human breast carcinoma cells, down-regulation of integrin alpha5beta1 and inhibition of epidermal growth factor receptor (EGFR) markedly reduced rates of cell proliferation. Mitotic cycle analysis showed that alpha5beta1 down-regulation resulted in cell cycle arrest at the S phase, followed by a significant increase in the population of apoptotic cells (subG1 population). Inhibition of EGFR activity also caused cell cycle arrest at the S-phase but without any increase in the subG1 population. Down-regulation of alpha5beta1 and EGFR inhibition resulted in a significant decrease of cell content of the active (phosphorylated) forms of FAK and Erk protein kinases. The data obtained suggest that alpha5beta1 integrin is implicated in cell growth control via inhibition of apoptotic cell death and through EGFR activation.

Breast cancer is the most frequent cancer and the leading cause of cancer-related deaths in women worldwide. We determined the expression of COX2, COX1, 15-HPGDH mRNA and miRNAs (miR-21, miR-155) in three estrogen positive human breast cancer cell lines (MCF-7, BT-474, ZR-75-1). According to the results of three independent experiments the amount of COX1 and COX2 mRNA was significantly higher in the ZR-75-1 than in MCF-7 and BT-474 cells. Levels of total 15-HPGDH; functional 15-HPGDH mRNA in BT-474 cell line were lower than in MCF-7 and ZR-75-1 ones. The synthesis of 15-HPGDH enzyme in BT-474 line was blocked at the nuclear immature pre-mRNA processing level. miR-155 expression level was significantly lower than miR-21 in breast cancer cell lines. Correlations between the dysregulation of miR-21, miR-155 and 15-HPGDH, COX-1, COX-2 mRNA were identified. Expression of miR-21 was high in MCF-7, ZR-75-1 and BT-474 cell lines. Our results show that miR-21 and miR-155 regulate activity of several genes in cancer cells, their effect on the individual genes was in some cases cumulative. Based on our results, we concluded that miR-21, miR-155 suppress the work of tumor suppressor gene 15-HPGDH and induce potential oncogene COX-2 that promotes cell malignancy and metastasis of breast cancer.

This review summarizes the clinical trials of the relationship of gene expression and protein ABC-transporters in breast cancer with the response to neoadjuvant chemotherapy (NAC) and survival of patients. In a large clinical material is considered the pre-treatment multidrug resistance (MDR) and adaptive MDR, that occurs in tumor cells during chemotherapy. Association pre-treatment MDR with NAC efficiency and survival is highly variable and not well-established. In all clinical trials, adaptive MDR showed a good association with NAC efficiency and survival of patients. The own results showed that 5-year distant metastasis-free survival was 73-78% and good response to NAC in patients with a decrease in ABC- expression. The up-regulation of these genes during NAC was related to a significant decrease (up to 50-55%) in metastasis-free survival and poor response to NAC. In the development of strategies to overcome MDR phenotype it is concluded based on the submitted clinical data.

Accumulation of doxorubicin (Dox), its conjugates with the second generation dendritic polymer (G2-Dox) and vector pro- tein (recombinant third domain of alpha-fetoprotein - 3D-G2- Dox) in normal and tumor cells was studied in vitro within the framework of the development of selective transport system of anticancer drugs to the target cells. The objects of the study were cells of peripheral blood mononuclear fraction of healthy donors and cells of breast adenocarcinoma lines MCF-7 and MCF-7/MDR1, differing in chemosensitivity. G2-Dox and 3D-G2-Dox accumulated in tumor cells of the both lines better than free Dox (p<0,05). However removal of these drugs out of cells MCF-7 and MCF-7/MDR1 was significantly different: in the latter case all free Dox was excluded from the cells for 24 hours while Dox, accumulated in composition with dendrimers, still remained in the cells. It was important that 3D-G2-Dox (unlike the G2-Dox) accumulated in normal cells worse than free Dox (p<0.01). Thus, the results indicate that the use of 3D-G2-Dox is the most promising because it accumulates in tumor cells better and in normal cells worse than free Dox. Furthermore it can be assumed that the use of 3D-G2-Dox would be especially useful in cases of multi-drug resistance associated with the high expression of P-glycoprotein.

There were performed researches on morphometric (the nuclear area, perimeter, the maximum and minimum diameters) and densitometric (optical density, integrated optical density) parameters of nuclei of cells on the cytologic smears received from 28 patients with atypical hyperplasia and an initial breast cancer. Significant reduction of measured nuclei parameters was noted among: moderately - and high-grade ductal carcinoma in situ, atypical ductal hyperplasia, lobular carcinoma in situ, an invasive papillary cancer, intraductal papilloma. The lowest value of the measured parameters was noted at love-grade ductal carcinoma in situ and intraductal papillary cancer. It was established that morphometric and densitometric indicators at atypical hyperplasia of an epithelium and an initial breast cancer in some cases overlap each other that is at the bottom of difficulties of differential cytomorphological diagnostics and quite often forces to formulate the cytologic conclusion in the presumable form.

In this paper we investigated the effect of RHAMM-target peptides on the invasion of breast cancer cells (MDA-MB-231). Cells were plated on gelatin substrate, Cy3-fluorescein-labeled, and then simultaneously processed with RHAMM-target peptides. Invasion of the cells was assessed by quantitative analysis of the area degradation of gelatin, using ImageJ software. We have found that RHAMM-target peptides inhibited the invasion of tumor cell by - 80% at a concentration of 10μg/ml (2x10⁻⁷ M). By confocal microscopy we also showed that a population of cancer cells was heterogeneous and composed from small cells (invasive) and large cells, non-invasive cells with 4-5 nucleus in the cytoplasm. We found that treatment of cells with RHAMM-target peptides led to a decrease in the number of cells of large size and induced structural disorganization of actin and enhanced amount of stress-fibers of actin.

We studied ability of TMA technique as alternative to analysis of whole sections (WS) for breast carcinomas. The study included 229 patients with breast carcinoma T1-2 N0 M0 treated within 2000-2009 years. After whole slide scanning were constructed TMA blocks using 2mm punches and TMA master device (3DHistech, Budapest). TMA results of immunohistochemistry of HER2 were compared retrospectively with the results of WS. General distribution of HER2 status for WS was: negative (0+1) 85,5%, unequal (2+) 6,07%, positive (3+) - 8.41%, for TMA cores negative (0+1) 82,6%, unequal (2+) 7,04%, positive (3+) - 10,33%. When we compared each cases for HER2 there was moderate agreement with negative (score 0) and positive(score 3+) case around 70% and poor agreement in HER2 (1+2+ category) - only 50% 25% including both false negative and false positive estimations. We thought such kind disagreement in individual group was due to using different primary antibodies (all not FDA-approved) in previous years compared with PATHWAY® rmAb 4B5 (Ventana) antibody which was used for TMA slides. For breast cancer TMAs could be reasonable alternative to WS. Especially for Her2 testing, should be used only FDA approved systems and this technique allow reduce time, reagent and finally cost of such type of analysis.

Whole-genome expression analysis methods significantly clarified contemporary breast cancer classification. Besides today clinical practice lacks the use of expression methods due to complexity of conduction, analysis and lack of clinical application. Further studies of breast cancer expression characteristics and clinical trials with stratification based of phonotypical features may improve the results of existing anticancer agents. Creation of limited clinically applicable test system, which incorporates all the specific breast cancer subtypes is currently needed.

High heterogeneity is characteristic of oncology diseases, often complicating the choice of optimal anticancer treatment. One cancer type may combine tumors differing in histogenesis, genetic lesions, and mechanism of cell transformation. Differences in the mechanism of cell malignant transformation result in specifics of cancer cell metabolism and sensitivity to various agents, including anticancer treatments. Hence, the molecular subtype of a tumor is essential to know for choosing the optimal therapeutic strategy. The review considers the role actin-associated proteins and tyrosine kinases, in particular, PDLIM4 and Src kinase, play in the formation of pathological signaling pathways.

This manuscript includes an update on the latest developments in the biology of breast cancer as well as the most recent advances in prevention and multidisciplinary management of this disease: surgery after neoadjuvant chemotherapy and anti-HER2 therapy of HER2 positive breast cancer, neoadjuvant and adjuvant endocrine treatment of ER+ (Luminal A) breast cancer. Our task (as in the St. Gallen and ESMO consensus recommendations) is to assist physicians to improve both therapy impact in patients and their results.

The review considers the effect of progestins on the function, proliferation, and apoptosis of cells of various organs in health and noncancerous disorders. Data are summarized to describe the mechanism of progestin action through various progesterone receptors and sensors and the regulation of their levels. The effects of progestins depend on the cell phenotype, including the composition and proportion of different receptors, activity of signaling pathways, and expression of transcription factor coregulators and steroid metabolism enzymes. The role paracrine regulation plays in the progestin effect is described. Particular attention is paid to the progestin effect on the tissues where progestins are thought or known to affect carcinogenesis or to stimulate or suppress the tumor growth, that is, to modulate cell proliferation, apoptosis, and the epithelial-mesenchymal transition.

The review gives data on the structure of cadherin cell adhesion molecules, their role in the body's development and malignant tumor progression. It describes cadherins that are considered to play the most important role in the development of a tumor process: E-, P-, and N-cadherins that belong to type I classical cadhedrins and VE-cadhedrin that does to type II cadherins. Particular emphasis is placed on the signal mechanisms with involvement of cadherins and cadherin-related molecules, which are realized in the body in health and in tumor transformation of cells.

The transcriptomic profiles of human breast cancer cell lines MCF-7 and MDA-MB-435 were investigated using the next-generation RNA sequencing (RNA-Seq). The DESeq package was used to screen the differentially expressed transcripts. A total of 229 genes with a significantly differential expression in MDA-MB-435 cells as compared with MCF-7 cells were obtained. Annotation of the biological functions of these genes through the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.7 demonstrated that the 229 differentially expressed genes were mainly implicated in the biological functions related to cell adhesion and motion, antigen processing and presentation (via MHC class II), hormone response, extracellular structure organization, tissue remodeling, and cell proliferation regulation. Analysis of the individual genes demonstrated that MDA-MB-435 cells exhibited a higher tendency to metastasis and antigen processing and presentation, and lower ability to hormone response. Twenty most abundant transcripts in MDA-MB-435 cells, such as VIM, TNC, and CD74, represent its high potential for metastasis. Besides the genes previously reported to be involved in tumor metastasis and development, genes newly identified in this study could provide new clues for the diagnosis and prognosis of aggressive breast cancers.

In our work we studied the effect of T lymphocytes and interferon-gamma on the vital activity of the breast cancer cells population and formation of multicellular tumor spheroids. We demonstrated the stages of multicellular tumor spheroids formation and the possible ways to implement antitumor influence of T lymphocytes and interferon-gamma through a change in estrogen receptor and the epidermal growth factor receptor expression. Our results shown a correlation between the type of humoral influance, the degree of expression of estrogen receptor and epidermal growth factor receptor and the intensity of tumor microaggregates formation.

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

Peculiarities of tumoral stroma, the indices of overall survival (OS) and disease free survival (DFS) were studied up in patients, suffering luminal mammarial gland cancer MGC type A. If the stroma have had occupied more than 50% of the tumor square, the OS and DFS indices were the highest. The link was established between the OS and DFS indices, the stromal square and expression of the MGC cells toward the estrogen and progesterone receptors. The pronounced stromal reaction was connected with the OS index improvement even in a less pronounced expression to estrogen and progesterone.

Recombinant adenovirus encoding the VP2 gene of infectious bursal disease virus (ADV-VP2) has shown potent anti-tumour effects due to its capability of apoptotic induction in cancer cells. In the present study, human breast cancer cells MCF-7 and MDA-MB-231 were infected with ADV-VP2. The expression of VP2 protein was registered 4 h post-infection, particularly in MCF-7 cells. Multiple time-point DNA ladder assay demonstrated that ADV-VP2 infected MDA-MB-231 and MCF-7 cells endured apoptosis as early as 8 and 12 h post-infection, respectively. Apoptosis induction in both MDA-MB-231 and MCF-7 cells, albeit different start points, lasted til 36 h post-infection. The induction of apoptosis by ADV-VP2 was further shown by the TUNEL assay, with dark brown discoloration of apoptotic cells. The present study also explored the different stages of apoptosis by Annexin V/PI double staining flow cytometry quantification. Treated MCF-7 and MDA-MB-231 cells, respectively detected 25.58 +/- 9.02 and 14.51 +/- 3.12% of early apoptotic cells, 6.09 +/- 4.06 and 77.12 +/- 5.09% of late apoptotic cells. Results revealed that there were significant differences in the number of cells of both types which underwent early and late apoptosis. Significant differences were also observed among viable and apoptotic cells which have been post treated with ADV-VP2. The apoptotic effects of ADV-VP2 on human breast cancer cell lines were consistently demonstrated by three apoptosis detection methods. Therefore, a cancer vaccine basing on gene therapy could be developed in the near future using the present construct.

Radioprotection appeared to be an important problem of today due to atom energetic development and utilization of radiation material in the industry, science and medicine. It has been shown that mitochondrial targeted antioxidant SkQR1 could attenuate radiation injury of human erythroleukemia K562 cells. Pretreatment with SkQR1 before irradiation decreased DNA double strand breaks formation, diminished the number of chromosomal aberrations and suppressed delayed ROS production. Prevention of oxidative stress and normalization of mitochondrial function by mitochondria-targeted antioxidants may be a potential therapeutic strategy not only against immediate consequences of radiation, but, either against its late consequences such as genomic instability. SkQR1 did not protect against radiation-induced damage the K562 subline with high level of multidrug resistance (MDR) due to SkQR1 extrusion with Pgp 170 MDR pump. We suggest that mitochondria-targeted antioxidants might be used for selective protection of normal cells against radiation-induced damage without interference with radiotherapy of MDR-positive tumors.

A decision regarding adjuvant chemotherapy in early (operable) breast cancer in the past was made entirely on the basis of clinical and pathological features. However with the growing awareness of tumor biology and the possibility of the genomic analysis to determine the molecular subtypes of breast cancer it is getting real to identify patients whose tumors are resistant to chemotherapy or vice versa benefit from its addition. Despite the fact that genomic analysis allows some patients avoiding chemotherapy (especially patients with localized breast cancer), such studies do not indicate the most appropriate chemotherapy regimens. Therefore treatment decisions should be based on a combination of biological features of the tumor, its stage and signs that characterize the patient such as age and tolerance to the side effects of therapy.

The state of the viscosity of erythrocyte membranes in breast cancer patients (68--in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type.

Experience of treatment in 2010-2012 yrs of the patients, suffering mammarial gland tumors, in The Center of Reconstructive and Restoration Medicine (The University Clinic) of The Odessa National Medical University was analyzed. There were examined 143 women with morphologically confirmed mammarial gland cancer (MGT), 56--benign mammary gland tumors and 50 healthy women. Molecular-genetic investigation was performed in the patients-women: there were determined the gene C634G polymorphism of VEGF and of the gene G308A of TNF--a with subsequent estimation of correlation of the mutations quantity and the mammarial gland diseases rate. Algorithm of differential diagnosis of benign tumors must include estimation of polymorphism of the VEGF gene C634G. While revealing of the heterozygous or homozygous bearers of mutation with the gene C634G polymorphism of VEGF the risk of the MGC occurrence is enhancing, what may serve as additional criterion for expedience for conduction of operative treatment in such patients.

We have previously shown that Snail, a regulator of epithelial-mesenchymal transition, is activated in the hypoxia-resistant breast cancer cell line HBL100. The purpose of this study was to evaluate the role of beta-catenin signaling pathway in the maintenance of breast cancer cells 'tolerance to hypoxia. The breast cancer cell lines MCF-7 and HBL-100 were used in this study; HBL-100 cells were characterized by increased resistance to hypoxia. We have demonstrated that the transcription factor beta-catenin is activated in hypoxic conditions and the beta-catenin activity is supported by Snail, a regulator of epithelial-mesenchymal transition. The activated beta-catenin regulates the expression of genes of the cell response to hypoxia and thus, it maintains the growth of breast cancer in the reduced oxygen conditions. The coordinated activation of Snail/beta-catenin/HIF-1alpha proteins in cell may be considered as an important factor of tumor resistance to hypoxia.

New approaches to the molecular classification of breast cancer are considered. Particular emphasis is placed on its basal-like type that belongs to the most aggressive and prognostically unfavorable forms of tumor. The origin of this type of breast cancer is the subject of intense debate in the scientific community. There are three basic theories that basal-like breast carcinoma may arise from the stem or myoepithelial cells and through dedifferentiation via epithelial-mesenchymal transformation. The theory of its origin from stem/progenitor cells is most valid and proven.

For the first time in a comparative perspective the epigenetic status of the benign proliferative processes, breast cancer, and metastases to regional lymph nodes was studied using DNA methylation microarray "GoldenGate Cancer Panel I" ("Illumina", USA). The functional groups of differentially methylated genes were identified in each set of samples. The genes that regulate cell proliferation and mobility were methylated in samples with benign proliferative processes. An aberrant methylation of the genes responsible for cell differentiation and proliferation, as well as protein phosphorylation and cell mobility was observed in the samples with malignant phenotype. Differential methylation of the genes that regulate cell adhesion, the formation of anatomical structures, angiogenesis, immune response, signal transduction, and protein phosphorylation was found in the samples with metastases to regional lymph nodes in comparison with the morphologically unaltered breast epithelium. The tissues from the benign proliferative processes and metastases to regional lymph nodes were generally characterized by a relatively lower level of epigenetic variability in comparison with the tissues of the primary tumor.

Targeted therapy (lapatinib and/or trastuzumab) in combination with chemotherapy (capecitabine) is highly effective in metastatic lesions of the brain in breast cancer patients with overexpress HER-2/neu. An objective response in the brain was achieved in 19 patients (55.9%). Complete regression was observed in 5 cases (14.7%), partial regression--14 (41.2%). Stabilization of tumor process in the brain was revealed in 12 patients (35.3%). There was marked improvement in the quality of life of the majority of patients due to the regression of symptoms and good tolerability of treatment.

The article presents the results of analysis of lymph and blood in 78 patients with breast cancer of I, II. III and IV stages. The content of total protein, albumins, globulins and fibrinogens was detected to study the protein balance in biological liquors under various stages of cancer. The results testify that in oncological patients it is essential to detect protein content of blood and peripheral lymph with subsequent adjustment.

It is well known that breast cancers (BC) are divided into 4 molecular genetic subgroups (luminal A, luminal B, HER2/neu-positive, and triple-negative (TNBC). The purpose of the investigation was to comparatively estimate the pattern of expression of Bcl-2, known as a good prognostic marker of BC, in different molecular genetic subgroups and to study the correlation of this protein with proliferative activity index and genetic aberrations on chromosome 17. The investigation covered 290 samples of invasive ductal BC. Bcl-2 expression was identified in 14% of HER2/neu-positive and TNBC cases while 77% of luminal B tumors and 100% of luminal A ones expressed Bcl-2. Loss of Bcl-2 expression correlated with clinically more aggressive BCs having a high proliferative activity and amplification of HER2/neu and chromosome 17 centromere. This may suggest the poor prognosis of luminal B, HER2/neu-positive and TNBC with no Bcl-2 expression and calls for further investigations on larger samples.

According to ASCO/CAP guidelines, there are two recommended methods for Her2/neu-testing in breast cancer patients such as immunohistochemistry and fluorescence in situ hybridization. This paper analyses results of alternative immunocytochemical method for Her2/neu detection and its diagnostic pitfalls.