Long Noncoding RNAs-LET Behave as a Noncoding Signature for Early-Onset Menarche and Late-Onset Menopause in Breast Cancer Patients

Background: Breast cancer (BC) as a major cause of cancer-related death in women shows a very complex molecular and clinical phenotype, which has reduced the effectiveness of medical interventions. Evidence suggests that long noncoding RNAs (lncRNAs) are responsible for an important part of this complexity. This study aims to assess the expression and clinical implication of lncRNA LET in the pathobiology of BC. Materials and Methods: Quantitative real-time polymerase chain reaction was used to measure the expression of lncRNA-LET in breast tumors and adjacent normal-appearing tissues from 4 BC patients, as well as normal mammary tissues. Moreover, a bioinformatics approach was applied to uncover the potential lncRNA-LET-mediated sponge regulatory network as LET/miRNA/mRNA crosstalk. Results: Our study revealed that lncRNA-LET was significantly down-expressed not only in breast tumors but also in normal appearing breast tissues samples from BC subjects compared with true normal breast tissues obtained from healthy women. The low level of lncRNA-LET was meaningfully associated with early-onset menarche (≤13 years) and late-onset menopause (≥50) in patients. Moreover, the bioinformatics analyses support that lncRNA-LET could function as a tumor suppressor miRNA sponge. Conclusion: The results indicate that normal appearing breast tissues can undergo tumor-related molecular changes. Furthermore, they reveal the potential role of the dysregulation in LET-mediated ceRNA network in the pathophysiology of BC.

Download Full-text

Repression of protocadherin 17 is correlated with elevated angiogenesis and hypoxia markers in female patients with breast cancer

Cancer Biomarkers ◽

10.3233/cbm-201593 ◽

2021 ◽

pp. 1-10

Author(s):

Sanaa A. El-Benhawy ◽

Samia A. Ebeid ◽

Nadia A. Abd El Moneim ◽

Rabie R. Abdel Wahed ◽

Amal R.R. Arab

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Clinical Stage ◽

Suppressor Gene ◽

Normal Breast ◽

Vital Role ◽

Control Group ◽

Breast Cancer Patients ◽

Cd34 Cells ◽

Breast Tissues

BACKGROUND: Altered cadherin expression plays a vital role in tumorigenesis, angiogenesis and tumor progression. However, the function of protocadherin 17 (PCDH17) in breast cancer remains unclear. OBJECTIVE: Our target is to explore PCDH17 gene expression in breast carcinoma tissues and its relation to serum angiopoietin-2 (Ang-2), carbonic anhydrase IX (CAIX) and % of circulating CD34+ cells in breast cancer patients (BCPs). METHODS: This study included Fifty female BCPs and 50 healthy females as control group. Cancerous and neighboring normal breast tissues were collected from BCPs as well as blood samples at diagnosis PCDH17 gene expression was evaluated by RT-PCR. Serum Ang-2, CAIX levels were measured by ELISA and % CD34+ cells were assessed by flow cytometry. RESULTS: PCDH17 was downregulated in cancerous breast tissues and its repression was significantly correlated with advanced stage and larger tumor size. Low PCDH17 was significantly correlated with serum Ang-2, % CD34+ cells and serum CAIX levels. Serum CAIX, Ang-2 and % CD34+ cells levels were highly elevated in BCPs and significantly correlated with clinical stage. CONCLUSIONS: PCDH17 downregulation correlated significantly with increased angiogenic and hypoxia biomarkers. These results explore the role of PCDH17 as a tumor suppressor gene inhibiting tumor growth and proliferation.

Download Full-text

Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

Breast Care ◽

10.1159/000489874 ◽

2019 ◽

Vol 14 (2) ◽

pp. 117-123 ◽

Cited By ~ 1

Author(s):

Kheirollah Yari ◽

Zohreh Rahimi

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Retinoic Acid Receptor ◽

Methylation Status ◽

Normal Breast ◽

Breast Cancer Patients ◽

Retinoic Acid Receptor Beta ◽

Cancer Tissues ◽

Breast Tissues ◽

Receptor Beta

Background: We aimed to determine the promoter methylation status of the retinoic acid receptor-beta 2 (RARβ2) gene among breast cancer patients and to review relevant studies in this field in various populations. Methods: We analyzed 400 samples which comprised blood specimens from 102 breast cancer patients, 102 first-degree female relatives of patients, 100 cancer-free females, 48 breast cancer tissues, and 48 adjacent normal breast tissues from the same patients. The RARβ2 methylation status was determined using methylation-specific polymerase chain reaction (MSP) and DNA sequencing methods. Results: The presence of combined partially methylated (MU) and fully methylated (MM) forms of the RARβ2 gene (MU+MM) in the blood of patients was associated with susceptibility to breast cancer (odds ratio = 4.7, p = 0.05). A significantly higher frequency of the MM genotype was observed in cancer tissue (10.4%) compared to matched adjacent normal breast tissue (0%) (p = 0.02). Conclusion: We found a higher frequency of RARβ2 gene methylation in the blood and cancer tissues of patients compared to the blood of controls and adjacent normal breast tissues. The survey of studies on various populations demonstrated a higher RARβ2 methylation frequency in breast cancer patients compared to normal individuals, and many reports suggest a significant association between hypermethylation of the gene and susceptibility to breast cancer.

Download Full-text

Direct Comparison of Metastasis-Related miRNAs Expression Levels in Circulating Tumor Cells, Corresponding Plasma, and Primary Tumors of Breast Cancer Patients

Clinical Chemistry ◽

10.1373/clinchem.2015.253716 ◽

2016 ◽

Vol 62 (7) ◽

pp. 1002-1011 ◽

Cited By ~ 30

Author(s):

Athina Markou ◽

Martha Zavridou ◽

Ioanna Sourvinou ◽

George Yousef ◽

Sofia Kounelis ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Peripheral Blood ◽

Breast Tumors ◽

Breast Cancer Patients ◽

Healthy Individuals ◽

Primary Tumors ◽

Expression Levels ◽

Breast Tissues

Abstract BACKGROUND Circulating tumor cells (CTCs) and microRNAs (miRNAs) are important in liquid biopsies in which peripheral blood is used to characterize the evolution of solid tumors. We evaluated the expression levels of miR-21, miR-146a, miR-200c, and miR-210 in CTCs of breast cancer patients with verified metastasis and compared their expression levels in corresponding plasma and primary tumors. METHODS Expression levels of the miRNAs were quantified by quantitative reverse transcription PCR (RT-qPCR) in (a) 89 primary breast tumors and 30 noncancerous breast tissues and (b) CTCs and corresponding plasma of 55 patients with metastatic breast cancer and 20 healthy donors. For 30 of these patients, CTCs, corresponding plasma, and primary tumor tissues were available. RESULTS In formalin-fixed, paraffin-embedded tissues, these miRNAs were differentially expressed between primary breast tumors and noncancerous breast tissues. miR-21 (P < 0.001) and miR-146a (P = 0.001) were overexpressed, whereas miR-200c (P = 0.004) and miR-210 (P = 0.002) were underexpressed. In multivariate analysis, miR-146a overexpression was significantly [hazard ratio 2.969 (1.231–7.157), P = 0.015] associated with progression-free survival. In peripheral blood, all miRNAs studied were overexpressed in both CTC and corresponding plasma. There was a significant association between miR-21 expression levels in CTCs and plasma for 36 of 55 samples (P = 0.008). In plasma, ROC curve analysis revealed that miR-21, miR-146a, and miR-210 could discriminate patients from healthy individuals. CONCLUSIONS Metastasis-related miRNAs are overexpressed in CTCs and corresponding plasma; miR-21 expression levels highly correlate in CTCs and plasma; and miR-21, miR-146a, and miR-210 are valuable plasma biomarkers for discriminating patients from healthy individuals.

Download Full-text

Nuclear ING3 Expression Is Correlated With a Good Prognosis of Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.589009 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiaoyan Wu ◽

Chuang Chen ◽

Bin Luo ◽

Dandan Yan ◽

Honglin Yan ◽

...

Keyword(s):

Breast Cancer ◽

Cox Regression ◽

Histological Grade ◽

Normal Breast ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Positive Type ◽

Cox Regression Analysis ◽

Cancer Tissues ◽

Breast Tissues

The inhibitor of growth (ING) family was discovered as the type II tumor suppressors, which regulated the proliferation, apoptosis, differentiation, angiogenesis, metastasis, and invasion of tumor cells through multiple pathways. ING3, a new member of ING family, has been reported to be downregulated in several types of tumors. However, few studies on ING3 in breast cancer have been reported. In this study, we investigated the expression of ING3 and determined its prognostic value in breast cancer. The immunohistochemistry was performed to evaluate the expression of ING3 in tissue microarrays (TMA) including breast cancer tissues (n=211) and normal breast tissues (n=50). In normal breast tissues, ING3 protein was detected in both the cytoplasm and nucleus. In breast cancer tissues, ING3 protein was principally detected in the cytoplasm. Compared with normal breast tissues, the expression of ING3 in nucleus was remarkably reduced in breast cancer tissues. The downregulated ING3 in nucleus was significantly correlated with clinicopathological characteristics including histological grade, lymph node metastasis, and the status of ER and PR. In HER2 positive-type and triple-negative breast cancer (TNBC) patients, it had the lower rate of nuclear ING3 with high expression than that in luminal-type. Moreover, Kaplan-Meier curves demonstrated that the reduced expression of ING3 in nucleus was correlated with a poorer 5-DFS and 5-OS of breast cancer patients. Importantly, multivariate Cox regression analysis suggested that the reduced expression of ING3 in nucleus was an independent prognostic factor in breast cancer. Our study comprehensively described the expression of ING3 in breast cancer for the first time and proved that it was an independent prognostic predictor of breast cancer, as well as a new idea for study of breast cancer.

Download Full-text

Frequency of Hsa-miR9 aberrant methylation in metastatic breast cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21092 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21092-e21092

Author(s):

Paola Parrella ◽

Anca Florescu ◽

Massimiliano Copetti ◽

Roberto Murgo ◽

Vanna Maria Valori ◽

...

Keyword(s):

Breast Cancer ◽

Promoter Region ◽

Regulation Of Gene Expression ◽

Metastatic Breast ◽

Mrna Translation ◽

Normal Breast ◽

Aberrant Methylation ◽

Breast Cancer Patients ◽

Breast Tissues

e21092 Background: MicroRNAs (miRNAs) are a recently discovered class of very small non-coding RNAs involved in the regulation of gene expression by interfereing with mRNA translation. It has been shown that human miR-9 expression levels are reduced in breast cancer samples due to the aberrant methylation of its promoter region . Methods: We analyzed74breast cancer cases treated by surgery at the IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. Pathological assessment included evaluation of histological type, grade and stage. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67 labeling index and Her2 amplification were also evaluated. Six of the 74 patients showed metastases at the diagnosis, and 8 patients developed metastases during the follow up. The median follow up time for the patients cohort was 44 months (range 28-57+). All metastatic patients (n=14) died from the disease. Genomic DNA extracted from 6 normal breast tissues obtained by reductive mammoplasty, and tumour samples was subjected to bisulphite treatment and the converted DNA was used as a template for MSP using primers specific for the methylated hsa-miR9 sequence. Results: Methylation at the hsa-miR9 promoter region was detected in 33 of 74 (44%) breast tumours and none of the 6 normal breast tissues (p=0.02). Interestingly, hsa-miR9 methylation was significantly more frequent in patients with syncronous or metachronous distant metastases (8 of 14, 57%) as compared with patients free from metastases (11 of 33, 32%) (p=0.02 χ2 Test). In particular, methylation was detected in all 5 tumours showing only bone metastases (100%), whereas methylation was less frequent (33%) in the group characterized by the the presence of visceral metastases (P=0.03 χ2 Test). Conclusions: Our results suggest that hsa-miR9 methylation in breast cancer is associated with tumour metastatic behaviour and might represent a novel biomarker for monitoring breast cancer patients.

Download Full-text

Reduced Expression of GPX3 in Breast Cancer Patients in Correlation with Clinical Significance

Global Medical Genetics ◽

10.1055/s-0040-1722170 ◽

2020 ◽

Vol 07 (03) ◽

pp. 087-091

Author(s):

Pensri Saelee ◽

Tanett Pongtheerat ◽

Thanet Sophonnithiprasert

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Prognostic Biomarker ◽

Normal Breast ◽

Breast Carcinogenesis ◽

Breast Cancer Patients ◽

Chain Reaction ◽

Messenger Ribonucleic Acid ◽

Polymerase Chain ◽

Breast Tissues

AbstractGlutathione peroxidase 3 (GPX3) is the main antioxidant enzyme in plasma. Its biological roles are to protect cells from oxidative stress-induced damage. Several studies have been reported the association between GPX3 expression and its correlation with cancer carcinogenesis including breast cancer. The aim of this research was to investigate the GPX3 messenger ribonucleic acid (mRNA) expression in 82 breast tumors and paired normal breast tissues by SYBR green quantitative real-time reverse transcription-polymerase chain reaction and the association with clinicopathological data. Our results show that GPX3 reduced expression was found significantly associated with number of metastatic lymph nodes (odds ratio [OR] = 3.41, 95% confidence interval [CI] = 1.35–8.64, p = 0.01), no distant metastasis (OR = 5.52, 95% CI = 3.74–11.89, p = 0.04), and nonhormone usage breast cancer patients (OR = 0.19, 95% CI = 0.04–0.93, p = 0.04). This finding suggested that GPX3 plays a role in breast carcinogenesis, and might serve as a prognostic biomarker in breast cancer patients.

Download Full-text

The roles of long noncoding RNAs in breast cancer metastasis

Cell Death and Disease ◽

10.1038/s41419-020-02954-4 ◽

2020 ◽

Vol 11 (9) ◽

Cited By ~ 1

Author(s):

Lingxia Liu ◽

Yu Zhang ◽

Jun Lu

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Noncoding Rnas ◽

Breast Cancer Metastasis ◽

Long Noncoding Rnas ◽

Breast Cancer Patients ◽

Breast Cancer Invasion ◽

Future Challenges

Abstract Breast cancer is the most significant threat to female health. Breast cancer metastasis is the major cause of mortality in breast cancer patients. To fully unravel the molecular mechanisms that underlie the breast cancer cell metastasis is critical for developing strategies to improve survival and prognosis in breast cancer patients. Recent studies have revealed that the long noncoding RNAs (lncRNAs) are involved in breast cancer metastasis through a variety of molecule mechanisms, though the precise functional details of these lncRNAs are yet to be clarified. In the present review, we focus on the functions of lncRNAs in breast cancer invasion and metastasis, with particular emphasis on the functional properties, the regulatory factors, the therapeutic promise, as well as the future challenges in studying these lncRNA.

Download Full-text

Portraying breast cancers with long noncoding RNAs

Science Advances ◽

10.1126/sciadv.1600220 ◽

2016 ◽

Vol 2 (9) ◽

pp. e1600220 ◽

Cited By ~ 55

Author(s):

Olivier Van Grembergen ◽

Martin Bizet ◽

Eric J. de Bony ◽

Emilie Calonne ◽

Pascale Putmans ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Transforming Growth Factor ◽

Noncoding Rnas ◽

Breast Tumors ◽

Long Noncoding Rnas ◽

Breast Cancers ◽

Mesenchymal Transition ◽

A Genome ◽

Wide Range

Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. We performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. We identified 215 lncRNAs whose genes are aberrantly expressed in breast tumors, as compared to normal samples. Unsupervised hierarchical clustering of breast tumors on the basis of their lncRNAs revealed four breast cancer subgroups that correlate tightly with PAM50-defined mRNA-based subtypes. Using multivariate analysis, we identified no less than 210 lncRNAs prognostic of clinical outcome. By analyzing the coexpression of lncRNA genes and protein-coding genes, we inferred potential functions of the 215 dysregulated lncRNAs. We then associated subtype-specific lncRNAs with key molecular processes involved in cancer. A correlation was observed, on the one hand, between luminal A–specific lncRNAs and the activation of phosphatidylinositol 3-kinase, fibroblast growth factor, and transforming growth factor–β pathways and, on the other hand, between basal-like–specific lncRNAs and the activation of epidermal growth factor receptor (EGFR)–dependent pathways and of the epithelial-to-mesenchymal transition. Finally, we showed that a specific lncRNA, which we called CYTOR, plays a role in breast cancer. We confirmed its predicted functions, showing that it regulates genes involved in the EGFR/mammalian target of rapamycin pathway and is required for cell proliferation, cell migration, and cytoskeleton organization. Overall, our work provides the most comprehensive analyses for lncRNA in breast cancers. Our findings suggest a wide range of biological functions associated with lncRNAs in breast cancer and provide a foundation for functional investigations that could lead to new therapeutic approaches.

Download Full-text

Expression Pattern of a Homeotic Gene, HOXA5, in Normal Breast and in Breast Tumors

Analytical Cellular Pathology ◽

10.1155/2006/974810 ◽

2006 ◽

Vol 28 (5-6) ◽

pp. 305-313

Author(s):

Gregory S. Henderson ◽

Paul J. van Diest ◽

Horst Burger ◽

Jose Russo ◽

Venu Raman

Keyword(s):

Breast Cancer ◽

Expression Pattern ◽

Breast Tumors ◽

Normal Breast ◽

Receptor Expression ◽

Homeotic Genes ◽

Breast Carcinomas ◽

Expression Levels ◽

Egfr Expression ◽

Breast Tissues

Introduction: Homeotic (HOX) gene products are now known to be functionally associated with breast cancer biogenesis. Recent evidence has indicated that HOXA5 regulates both p53 and progesterone receptor expression levels in breast cancer cells. In addition, HOXA5 has been shown to interact and regulate the activity of another protein referred to as Twist. As homeotic genes play a pivotal role in development, we sought to decipher the expression pattern in both normal breast tissues and in breast carcinomas. Methods: RT-PCR and immunohistochemistry were performed, to assay the levels of HOXA5 expression, on a panel of normal breast tissue and its corresponding primary breast tumors. Results and Conclusions: We show that HOXA5 expression was maintained at stable levels at different reproductive stages of a woman's life, except during lactation. This evidence indicates that HOXA5 may play a role in maintaining the differentiated state within the breast epithelium. However, nearly 70% of all breast carcinomas had decreased HOXA5 protein levels as compared to normal breast tissues. In addition, we demonstrate that HOXA5 protein expression levels in breast carcinomas inversely co-relates with Epidermal Growth Factor Receptor (EGFR) expression. Furthermore, we found that the survival rate amongst the different low levels of HOXA5 expressing breast tumors was not significant, indicative of an early tumorigenesis process in the absence of innate levels of HOXA5 in normal breast cells.

Download Full-text

Upregulation of miR-21 and miR-106b in plasma and tissues as a possible prognostic marker in aggressive breast cancer

10.32592/ircmj.2021.23.10.547 ◽

2021 ◽

Keyword(s):

Breast Cancer ◽

Ductal Carcinoma ◽

Reduction Mammoplasty ◽

Lymph Node Involvement ◽

Normal Breast ◽

Cancer Prognosis ◽

Mammary Tissue ◽

Control Group ◽

Breast Cancer Patients ◽

Breast Tissues

Background: The miRNAs are referred to small non-coding RNAs (consisting of 18 to 25 nucleotides). Functional studies have shown their functions to be oncogenes or tumor suppressor genes in different types of cancers. The miR-106b and miR-21 have been identified to participate in the biological behaviors of cells. This study aimed to evaluate the tissue and plasma levels of miR-21 and miR-106b in patients with breast cancer who were diagnosed with ductal carcinoma. Methods: In total, 40 cases of breast cancer patients 180 samples were examined in this project. Samples included ductal carcinoma breast tumors (n=40), normal breast tissues of the margin of the tumor (n=40) and 20 samples from unaffected mammary tissue of females undergoing reduction mammoplasty (control group), plasma samples of patients with breast cancer (n=40), and plasma of non-affected individuals (n=40). The expression levels of miR-106b and miR-21 were determined using SYBR Green real-time RT-PCR assay in breast tissues and plasma of cancerous patients in comparison to the controls. Results: MiR-106b and miR-21 revealed much higher expression in tissues and plasma of patients with breast cancer in comparison to that in the group of control (P<0.001). High levels of mir-106b and miR-21 expression in plasma and tumor tissues were highly correlated with tumors in higher stages and lymph node involvement (P<0.0001). Conclusions: Based on the obtained results, upregulation of miR-106b and miR-21 in the plasma of patients with breast cancer can act as a possible non-invasive biomarker for breast cancer prognosis. Further follow-up studies are required to confirm this.

Download Full-text