Child gigantomastia revealing juvenile giant fibroadenomas

Breast masses in children and adolescents are uncommon. They can be caused by tumors such as fibroadenomas and phyllode tumors. These masses can cause gigantomastia, due to their rapidly increasing size. We report the case of a 12 years old patient admitted in our department for a rapidly growing gigantomastia evolving in a matter of 8 months. Imaging features were in favor of juvenile giant fibroadenomas and diagnosis was confirmed by biopsy. Juvenile giant fibroadenomas are rare and represent 0.5–2% of all fibroadenomas, their exact aetiology is unknown. They affect children and adolescents, with a predominance in African-American females. They may cause breast enlargement and asymmetry. The rapid growth causes anxiety and is the main cause of consultation. These tumors although benign, have to be treated rapidly because they can destruct up to 80% of the surrounding normal breast tissue, and conservatory treatment cannot be done.

Identification of Novel CircRNA-miRNA-mRNA Regulatory Network and Its Prognostic Prediction in Breast Cancer

Aim. This study aimed to investigate the expression profiles of circRNAs and candidate circRNA-miRNA-mRNA network in BC. Methods. Differentially expressed circRNAs, miRNAs, and mRNAs (DEcircRNAs, DEmiRNAs, and DEmRNAs) between BC and normal breast tissue samples were screened by analyzing raw data of the RNA sequencing profile. The expression levels of hub genes in 48 pairs of cancerous and tumor-free breast tissues surgically resected from BC patients were determined by RT-qPCR analysis. Results. A total of 145 DEcircRNAs, 140 DEmiRNAs, and 2451 DEmRNAs between BC and normal breast tissue samples were screened out. There were 5 pairs of upcircRNA-downmiRNA-upmRNA network and 20 pairs of downcircRNA-upmiRNA-downmRNA network. EIF4EBP1, DUSP1, EGR2, EZH1, and CBX7 were found to be correlated with overall survival of the patients with BC. The expression level of EIF4EBP1 was increased and the expression levels of DUSP1, EGR2, EZH1, and CBX7 were decreased in cancerous breast tissues compared to tumor-free breast tissues p < 0.0001 . The RT-qPCR results from 48 BC patients were consistent with the bioinformatics results. Conclusion. This study provides a novel perspective to study circRNA-miRNA-mRNA network in BC and assists in the identification of new potential biomarkers to be used for diagnostic and prognostic purposes.

Comparative Analysis of Eosin-based Fluorescence Microscopy of Non-neoplastic Breast Tissue and Fibroadenoma

Background: Fibroadenoma (FA) is one of the most frequently diagnosed benign neoplasm in women. Various researches have reported increased risk of breast cancer in females with FA. It stems from the proliferation of epithelial and stromal contents of the terminal duct lobular units (TDLU`S) of breast tissue, that are the primary sites for the histopathologic assessment which is the gold standard for the diagnosis of disease. However, this method is subjective and possess interobserver variability. Therefore, new quantitative methods are required to aid in diagnosis. Hence we evaluated fluorescence light intensity and its use in histopatholgic evaluation. Aim: The goal of this research was to compare and quantify red and green fluorescence light intensities of ductal cells and stroma of non-neoplastic breast tissue with fibroadenomatous tissue. Method: A cross-sectional study was done in the Cell biology and histology lab of Ziauddin University. 44 slides of normal breast tissue and 44 slides of diagnosed fibroadenomatous tissue were taken from Dr Ziauddin Hospital, North Campus. Hematoxylin and eosin (H&E) staining of the slides were done following standard protocols. On microscopic examination, the changes in light intensities of ductal cells and stroma of normal breast tissue and fibroadenoma were quantified using dual channel fluorescence microscopy using Nikon NIS imaging software. Results: The results demonstrated statistically significant increase (p-value <0.05) in mean red (37.22±5.9) and green (22.47±6.6) light intensity of stroma in FA when compared with red (32.71± 6.7) and green (17.01±4.3) light intensity of normal breast tissue. Whereas, R/G ratio for normal tissue was higher (1.95±0.11) than R/G for FA (1.74±0.37) with a p value of <0.05. Similarly, for ductal cells; statistically significant (p value <0.05) increase in mean red (38.86±5.4) and green (15.54±2.51) light intensity for FA was found when compared with red (29.62±1.89) and green (12.60±1.67) intensity of normal tissue. R/G ratio for FA (2.5±0.24) was compared to be higher than normal tissue (2.36±0.3) with a p value of <0.05. Conclusion: The study suggests that fluorescence microscopy combined with quantitative assessment fluorescence light intensities may may be a helpful tool for histomorphic evaluation of the breast tissue.

Cancer Stem Cells and Somatic Stem Cells as Potential New Drug Targets, Prognosis Markers, and Therapy Efficacy Predictors in Breast Cancer Treatment

New drug targets, markers of disease prognosis, and more efficient treatment options are an unmet clinical need in breast cancer (BC). We have conducted a pilot study including patients with luminal B stage breast cancer IIA–IIIB. The presence and frequency of various populations of cancer stem cells (CSC) and somatic stem cells were assessed in the blood, breast tumor tissue, and normal breast tissue. Our results suggest that patients with BC can be divided into two distinct groups based on the frequency of aldehyde dehydrogenase positive cells (ALDH1+ cells) in the blood (ALDH1hi and ALDH1low). In the ALDH1hi cells group, the tumor is dominated by epithelial tumor cells CD44+CD24low, CD326+CD44+CD24−, and CD326−CD49f+, while in the ALDH1low cells group, CSCs of mesenchymal origin and epithelial tumor cells (CD227+CD44+CD24− and CD44+CD24−CD49f+) are predominant. In vitro CSCs of the ALDH1low cells group expressing CD326 showed high resistance to cytostatics, CD227+ CSCs of the ALDH1hi cells group are sensitive to cytostatics. Epithelial precursors of a healthy mammary gland were revealed in normal breast tissue of patients with BC from both groups. The cells were associated with a positive effect of chemotherapy and remission in BC patients. Thus, dynamic control of their presence in blood and assessment of the sensitivity of CSCs to cytostatics in vitro can improve the effectiveness of chemotherapy in BC.

Evidence of Accelerated Epigenetic Aging of Breast Tissues In Patients With Breast Cancer Is Driven By CpGs Associated With Polycomb Related Genes

Purpose: Age is one of the strongest risk factors for the development of breast cancer, however the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results: The Levine (p=0.0037) and Yang clocks (p=0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p=0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

The Role of Chronic Inflammation in the Development of Breast Cancer

Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis.

Changes in Immune Cell Types with Age in Breast are Consistent with a Decline in Immune Surveillance and Increased Immunosuppression

A majority of breast cancers (BC) are age-related and we seek to determine what cellular and molecular changes occur in breast tissue with age that make women more susceptible to cancer initiation. Immune-epithelial cell interactions are important during mammary gland development and the immune system plays an important role in BC progression. The composition of human immune cell populations is known to change in peripheral blood with age and in breast tissue during BC progression. Less is known about changes in immune populations in normal breast tissue and how their interactions with mammary epithelia change with age. We quantified densities of T cells, B cells, and macrophage subsets in pathologically normal breast tissue from 122 different women who ranged in age from 24 to 74 years old. Donor-matched peripheral blood from a subset of 20 donors was analyzed by flow cytometry. Tissue immune cell densities and localizations relative to the epithelium were quantified in situ with machine learning-based image analyses of multiplex immunohistochemistry-stained tissue sections. In situ results were corroborated with flow cytometry analyses of peri-epithelial immune cells from primary breast tissue preparations and transcriptome analyses of public data from bulk tissue reduction mammoplasties. Proportions of immune cell subsets in breast tissue and donor-matched peripheral blood were not correlated. Density (cells/mm2) of T and B lymphocytes in situ decreased with age. T cells and macrophages preferentially localized near or within epithelial bilayers, rather than the intralobular stroma. M2 macrophage density was higher than M1 macrophage density and this difference was due to higher density of M2 in the intralobular stroma. Transcriptional signature analyses suggested age-dependent decline in adaptive immune cell populations and functions and increased innate immune cell activity. T cells and macrophages are so intimately associated with the epithelia that they are embedded within the bilayer, suggesting an important role for immune-epithelial cell interactions. Age-associated decreased T cell density in peri-epithelial regions, and increased M2 macrophage density in intralobular stroma suggests the emergence of a tissue microenvironment that is simultaneously immune-senescent and immunosuppressive with age.

Identification of high-risk genes in triple-negative breast cancer by bioinformatics

Background Current research has failed to find a target gene for triple-negative breast cancer (TNBC), which has resulted in the treatment for TNBC being less effective than that for other types of breast cancer. Finding high-risk genes for TNBC by bioinformatics may help to identify target genes for TNBC. Methods The gene expression data of 4 chips (GSE7904, GSE31448, GSE45827, GSE65194) which contains of normal breast tissue and TNBC tissue were obtained from the Gene Expression Omnibus. The differentially expressed genes (DEGs) between normal breast tissue and TNBC tissue were identified. Gene Ontology (GO) functional annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were performed by the DAVID website. Protein-protein interaction network analysis of DEGs was carried out by the STRING website, and the results were imported into Cytoscape. Then, module analysis was carried out by using the MCODE app. The online tool of the Kaplan-Meier Plotter website was used to analyse associations between relapse-free survival (RFS) and the expression of genes obtained by MCODE, and the metastasis-free survival (MFS) data from GSE58812 were used for survival verification. The difference in the expression of the identified genes was verified by the online tool of the UALCAN website. Results There were 127 upregulated and 293 downregulated genes in the DEGs. The GO and KEGG analysis showed that the DEGs were particularly enriched in mitotic nuclear division, extracellular space, heparin binding, and ECM-receptor interaction. MCODE obtained a total of 47 genes in 4 gene clusters, 29 of which were related to RFS. Survival verification indicated that 14 out of 29 genes were related to MFS, namely, CCNB1, AURKB, KIF20A, BUB1B, DLGAP5, CXCL11, CXCL9, CXCL10, CXCL12, IGF1, FN1, CFD, SGO2 and CDCA5. Conclusions We identified 14 genes as the high-risk genes for TNBC. Further research on these genes may identify the target genes of TNBC.

Comprehensive Analysis of the Expression and Prognosis for DCTPP1 gene in Breast Cancer

Background: Breast cancer is a common malignancy in women. DCTPP1 is a potential target for the development of antitumor drugs, and plays an important role in the process of DNA replication. Aims: To investigate the biological role of DCTPP1 gene, as well as its expression in breast cancer and its relation to patient prognosis. Materials and Methods: Breast cancer data was derived from the TCGA database. Using the UALCAN database, the expression level of DCTPP1 mRNA in breast cancer tissues was investigated. The expression of DCTPP1 in various pathological types of breast cancer was studied using the Human Protein Atlas. UALCAN was also used to investigate the relationship between DCTPP1 gene expression and breast cancer patient prognosis. Bioinformatics studied the proteins related to DCTPP1 expression and their roles in the GeneMANIA and WebGestalt databases. Results: DCTPP1 mRNA was significantly expressed in breast cancer compared to normal breast tissue (P<0.001). DCTPP1 was shown to be highly expressed in breast cancer tissues from different pathological types and stages (P<0.001). The DCTPP1 protein was expressed at a higher frequency in breast cancer than in normal breast tissue. When compared to patients with low DCTPP1 expression, patients with high DCTPP1 expression had a considerably shorter overall survival time. The 20 proteins related to DCTPP1 expression were mostly located in the nucleus and membrane, and were involved in biological regulation, stimulus response, metabolic process, and other processes, according to gene ontology analysis. It plays an important role in protein binding, ion binding, and nucleic acid binding. Conclusion: DCTPP1 is highly expressed in breast cancer, and is associated to a poor prognosis for patients with breast cancer. DCTPP1 may be a potential therapy and intervention target for breast cancer.