miRNAs In Breast Cancer Progression Research Articles

Functions of Differentially Regulated miRNAs in Breast Cancer Progression: Potential Markers for Early Detection and Candidates for Therapy.

Breast cancer remains a major global health concern, emphasizing the need for reliable biomarkers to enhance early detection and therapeutic interventions. MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNA (~22 nt in length) molecules, which are aberrantly expressed in cancer and seem to influence tumor behavior and progression. Specific miRNA dysregulation has been associated with breast cancer initiation, proliferation, invasion, and metastasis. Understanding the functional roles of these miRNAs provides valuable insights into the intricate molecular mechanisms underlying breast cancer progression. The diagnostic potential of miRNAs as non-invasive biomarkers for early breast cancer detection is a burgeoning area of research. This review aims to elucidate the functions of differentially regulated miRNAs in breast cancer progression and assess their potential as markers for early detection, stage-specific biomarkers, and therapeutic targets. Furthermore, the ability of specific miRNAs to serve as prognostic indicators and predictors of treatment response highlights their potential clinical utility in guiding personalized therapeutic interventions.

The Emerging Roles of Exosomal miRNAs in Breast Cancer Progression and Potential Clinical Applications.

Breast cancer remains the leading malignancy in terms of morbidity and mortality today. The tumor microenvironment of breast cancer includes multiple cell types, secreted proteins, and signaling components such as exosomes. Among these, exosomes have a lipid bilayer structure. Exosomes can reflect the biological traits of the parent cell and carry a variety of biologically active components, including proteins, lipids, small molecules, and non-coding RNAs, which include miRNA, lncRNA, and circRNA. MiRNAs are a group of non-coding RNAs of approximately 20-23 nucleotides in length encoded by the genome, triggering silencing and functional repression of target genes. MiRNAs have been shown to play a significant role in the development of cancer owing to their role in the prognosis, pathogenesis, diagnosis, and treatment of cancer. MiRNAs in exosomes can serve as effective mediators of information transfer from parental cells to recipient cells and trigger changes in biological traits such as proliferation, invasion, migration, and drug resistance. These changes can profoundly alter the progression of breast cancer. Therefore, here, we systematically summarize the association of exosomal miRNAs on breast cancer progression, diagnosis, and treatment in the hope of providing novel strategies and directions for subsequent breast cancer treatment.

The Intricate Interplay between Cancer Stem Cells and Oncogenic miRNAs in Breast Cancer Progression and Metastasis.

Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, overcome cell senescence, and proliferate in an uncontrolled manner. Both clinical samples and cancer cell lines provide researchers with an insight into the complex structure and hierarchy of cancer. Intratumor heterogeneity allows for multiple cancer cell subpopulations to simultaneously coexist within tumors. One category of these cancer cell subpopulations is cancer stem cells (CSCs), which possess stem-like characteristics and are not easily detectable. In the case of breast cancer, which is the most prevalent cancer type among females, such subpopulations of cells have been isolated and characterized via specific stem cell markers. These stem-like cells, known as breast cancer stem cells (BCSCs), have been linked to major events during tumorigenesis including invasion, metastasis and patient relapse following conventional therapies. Complex signaling circuitries seem to regulate the stemness and phenotypic plasticity of BCSCs along with their differentiation, evasion of immunosurveillance, invasiveness and metastatic potential. Within these complex circuitries, new key players begin to arise, with one of them being a category of small non-coding RNAs, known as miRNAs. Here, we review the importance of oncogenic miRNAs in the regulation of CSCs during breast cancer formation, promotion and metastasis, in order to highlight their anticipated usage as diagnostic and prognostic tools in the context of patient stratification and precision medicine.

Advances of Exosomal miRNAs in Breast Cancer Progression and Diagnosis.

Breast cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer death in women worldwide. Although many factors associated with breast cancer have been identified, the definite etiology of breast cancer is still unclear. In addition, early diagnosis of breast cancer remains challenging. Exosomes are membrane-bound nanovesicles secreted by most types of cells and contain a series of biologically important molecules, such as lipids, proteins, and miRNAs, etc. Emerging evidence shows that exosomes can affect the status of cells by transmitting substances and messages among cells and are involved in various physiological and pathological processes. In breast cancer, exosomes play a significant role in breast tumorigenesis and progression through transfer miRNAs which can be potential biomarkers for early diagnosis of breast cancer. This review discusses the potential utility of exosomal miRNAs in breast cancer progression such as tumorigenesis, metastasis, immune regulation and drug resistance, and further in breast cancer diagnosis.

The role of vulpinic acid as a natural compound in the regulation of breast cancer-associated miRNAs

BackgroundBreast cancer is the most frequently diagnosed cancer, and no effective treatment solution has yet been found. The number of studies based on the research of novel natural compounds in the treatment of breast cancer has been increasing in recent years. The anticancer properties of natural compounds are related to the regulation of microRNA (miRNA) expression. Therefore, changing the profile of miRNAs with the use of natural products is very important in cancer treatment. However, the role of vulpinic acid and related miRNAs in breast cancer progression remains unknown. Vulpinic acid, methyl (as2E)-2-(3-hydroxy-5-oxo-4-phenylfuran-2-ylidene)-2 phenylacetate, is a natural product extracted from the lichen species and shows an anticancer effect on different cancer cells.MethodsThis study examines the effects of vulpinic acid on the miRNA levels of breast cancer (MCF-7) cells and its relationship with cell proliferation and apoptosis levels. The antiproliferative effect of vulpinic acid was screened against MCF-7 breast cancer cells and MCF-12A breast epithelial cells using the xCELLigence real-time cell analysis system. We analyzed the altered miRNA expression profile in MCF-7 breast cancer cells versus MCF-12A cells following their response to vulpinic acid through microarray analysis. The microarray analysis results were confirmed through quantitative real-time PCR and bioinformatics analysis.ResultsThe results of the miRNA array and bioinformatic analyses demonstrated that 12 miRNAs were specifically responsive to vulpinic acid in MCF-7 breast cancer cells. This is the first study to reveal that vulpinic acid inhibits the expression of 12 miRNAs and suppresses breast cancer cell proliferation. The study also revealed that vulpinic acid may downregulate the expression of 12 miRNAs by repressing the FOXO-3 gene. The miRNA targets were mainly found to play a role in the apoptosis, cell cycle and MAPK pathways. Moreover, Bcl-2, Bax, procaspase-3 and procaspase-9 protein levels were assessed by western blot analysis for validation of apoptosis at the protein level.ConclusionThis study revealed the molecular mechanisms of vulpinic acid on breast cancer and showed that vulpinic acid regulates apoptosis signaling pathways by decreasing the expression of miRNAs. The miRNA expression patterns illuminate the underlying effect of vulpinic acid in breast cancer treatment.Graphical

Pax-5 Inhibits Breast Cancer Proliferation Through MiR-215 Up-regulation.

In breast cancer, Pax-5 promotes pro-epithelial features and suppresses malignant cancer processes. However, the molecular mechanism of this antitumor activity remains largely unknown. This study aimed to identify the cellular roles of Pax-5-regulated miRNAs in breast cancer progression. After transient transfection of Pax-5 in MDA-MB-231 breast cancer cells, Pax-5-regulated miRNA expression was examined by next-generation sequencing. The identified Pax-5-regulated miRNAs were then validated by qRT-PCR and examined for the roles they play in breast cancer cells. Pax-5 was shown to be an effective modulator of miR-215-5p and its target genes. MiR-215 inhibited cell proliferation and migration of breast cancer cells, but not cell invasion. More importantly, Pax-5-induced suppression of cancer cell proliferation and migration was found to be miR-215-dependent. Interestingly, miR-215 profiling in clinical tumor samples showed that miR-215 expression was lower in cancer tissues in comparison to healthy controls. Pax-5 reduces breast cancer proliferation and migration through up-regulation of the tumor suppressor miR-215. This result supports the use of miR-215 as a prognostic marker for breast cancer.

Functional miRNAs in breast cancer drug resistance.

Owing to improved early surveillance and advanced therapy strategies, the current death rate due to breast cancer has decreased; nevertheless, drug resistance and relapse remain obstacles on the path to successful systematic treatment. Multiple mechanisms responsible for drug resistance have been elucidated, and miRNAs seem to play a major part in almost every aspect of cancer progression, including tumorigenesis, metastasis, and drug resistance. In recent years, exosomes have emerged as novel modes of intercellular signaling vehicles, initiating cell–cell communication through their fusion with target cell membranes, delivering functional molecules including miRNAs and proteins. This review particularly focuses on enumerating functional miRNAs involved in breast cancer drug resistance as well as their targets and related mechanisms. Subsequently, we discuss the prospects and challenges of miRNA function in drug resistance and highlight valuable approaches for the investigation of the role of exosomal miRNAs in breast cancer progression and drug resistance.

MiRNAs as potential biomarkers in early breast cancer detection following mammography.

Breast cancer is the most common cancer among American women, except for skin cancers. About 12 % women in the United States will develop invasive breast cancer during their lifetime. Currently one of the most accepted model/theories is that ductal breast cancer (most common type of breast cancer) follows a linear progression: from normal breast epithelial cells to ductal hyperplasia to atypical ductal hyperplasia (ADH) to ductal carcinoma in situ (DCIS), and finally to invasive ductal carcinoma (IDC). Distinguishing pure ADH diagnosis from DCIS and/or IDC on mammography, and even combined with follow-up core needle biopsy (CNB) is still a challenge. Therefore subsequent surgical excision cannot be avoided to make a definitive diagnosis. MicroRNAs (miRNAs) are a highly abundant class of endogenous non-coding RNAs, which contribute to cancer initiation and progression, and are differentially expressed between normal and cancer tissues. They can function as either tumor suppressors or oncogenes. With accumulating evidence of the role of miRNAs in breast cancer progression, including our own studies, we sought to summarize the nature of early breast lesions and the potential use of miRNA molecules as biomarkers in early breast cancer detection. In particular, miRNA biomarkers may potentially serve as a companion tool following mammography screening and CNB. In the long-term, a better understanding of the molecular mechanisms underlying the miRNA signatures associated with breast cancer development could potentially result in the development of novel strategies for disease prevention and therapy.

MiR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer.

IntroductionTriple-negative breast cancer (TNBC) represents 15 to 20% of all types of breast cancer; however, it accounts for a large number of metastatic cases and deaths, and there is still no effective treatment. The deregulation of microRNAs (miRNAs) in breast cancer has been widely reported. We previously identified that miR-638 was one of the most deregulated miRNAs in breast cancer progression. Bioinformatics analysis revealed that miR-638 directly targets BRCA1. The aim of this study was to investigate the role of miR-638 in breast cancer prognosis and treatment.MethodsFormalin-fixed, paraffin-embedded (FFPE) breast cancer samples were microdissected into normal epithelial and invasive ductal carcinoma (IDC) cells, and total RNA was isolated. Several breast cancer cell lines were used for the functional analysis. miR-638 target genes were identified by TARGETSCAN-VERT 6.2 and miRanda. The expression of miR-638 and its target genes was analyzed by real-time qRT-PCR and Western blotting. Dual-luciferase reporter assay was employed to confirm the specificity of miR-638 target genes. The biological function of miR-638 was analyzed by MTT chemosensitivity, matrigel invasion and host cell reactivation assays.ResultsThe expression of miR-638 was decreased in IDC tissue samples compared to their adjacent normal controls. The decreased miR-638 expression was more prevalent in non-TNBC compared with TNBC cases. miR-638 expression was significantly downregulated in breast cancer cell lines compared to the immortalized MCF-10A epithelial cells. BRCA1 was predicted as one of the direct targets of miR-638, which was subsequently confirmed by dual-luciferase reporter assay. Forced expression of miR-638 resulted in a significantly reduced proliferation rate as well as decreased invasive ability in TNBC cells. Furthermore, miR-638 overexpression increased sensitivity to DNA-damaging agents, ultraviolet (UV) and cisplatin, but not to 5-fluorouracil (5-FU) and epirubicin exposure in TNBC cells. Host cell reactivation assays showed that miR-638 reduced DNA repair capability in post UV/cisplatin-exposed TNBC cells. The reduced proliferation, invasive ability, and DNA repair capabilities are associated with downregulated BRCA1 expression.ConclusionsOur findings suggest that miR-638 plays an important role in TNBC progression via BRCA1 deregulation. Therefore, miR-638 might serve as a potential prognostic biomarker and therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0435-5) contains supplementary material, which is available to authorized users.

Activin and TGFβ regulate expression of the microRNA-181 family to promote cell migration and invasion in breast cancer cells

MicroRNA-181 (miR-181) is a multifaceted miRNA that has been implicated in many cellular processes such as cell fate determination and cellular invasion. While miR-181 is often overexpressed in human tumors, a direct role for this miRNA in breast cancer progression has not yet been characterized. In this study, we found this miRNA to be regulated by both activin and TGFβ. While we found no effect of miR-181 modulation on activin/TGFβ-mediated tumor suppression, our data clearly indicate that miR-181 plays a critical and prominent role downstream of two growth factors, in mediating their pro-migratory and pro-invasive effects in breast cancer cells miR-181 acts as a metastamir in breast cancer. Thus, our findings define a novel role for miR-181 downstream of activin/TGFβ in regulating their tumor promoting functions. Having defined miR-181 as a critical regulator of tumor progression in vitro, our results thus, highlight miR-181 as an important potential therapeutic target in breast cancer.