microRNAs in breast cancer development and treatment

microRNAs (herein after miRNAs) represent a recently uncovered class of small and endogenous non-coding RNAs. miRNAs play a well conserved and crucial role in normal biological processes, such as cell differentiation, proliferation and apoptosis through a complicated gene regulation networking. The recent rise of interest in miRNAs in cancer research is ascribed to the breakthrough of their role in many pathological processes, including malignant transformation. miRNAs signatures have been clearly defined for certain types of cancer, with correlation to tumor aggressiveness, therapy response and patient outcome. Furthermore, the use of miRNAs as therapeutic targets for cancer is currently under investigation. The aim of this review is to focus on the role of miRNAs in breast cancer development and to summarize the evidence for their potential diagnostic and therapeutic applications in clinical practice.     

Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management

MicroRNAs (miRNAs) are an emerging class of gene expression modulators with relevant roles in several biological processes, including cell differentiation, development, apoptosis, and regulation of the cell cycle. Deregulation of those tiny RNA molecules has been described frequently as a major determinant for the initiation and progression of diseases, including cancer. Not only miRNAs but also the enzymes responsible for miRNA processing could be deregulated in cancer. In this review, we address the role of miRNAs in the pathogenesis of breast cancer, since there are oncogenic, tumor-suppressive, and metastatic-influencing miRNAs. Additionally, the different detection platforms and normalization strategies for miRNAs will be discussed. The major part of this review, however, will focus on the capability of miRNAs to act as diagnostic, predictive, or prognostic biomarkers. We will give an overview of their potential to correlate with response to or benefit from a given treatment and we will consider their ability to give information on prognosis in breast cancer. We will focus on miRNAs validated by more than one study or verified in independent cohorts or where results rely on preclinical as well as clinical evidence. As such, we will discuss their potential use in the personalized management of breast cancer.     

Regulation of epithelial-mesenchymal transition through microRNAs: clinical and biological significance of microRNAs in breast cancer

Breast cancer is a malignant disease to treat among female worldwide due to its high capability to metastasize and mutate. Epithelial-mesenchymal transition is one of the essential processes involved in the metastatic capacity of breast cancer. In the recent time, the studies demonstrate that microRNAs, a kind of small non-coding RNA molecules, could be served as negative regulators in breast cancer, regulating cell cycle, drug resistance, and the process of metastasis in cancer development. With the assistance of microRNA profiling, the study concentrating on the regulatory function of miRNAs in breast cancer could be investigated more effectively and efficiently. More recent studies demonstrate that miRNAs have an important role to play in the EMT process of breast cancer to modulate metastasis. This small essay is on the purpose of demonstrating the significance and detection of miRNAs in breast cancer EMT process as oncogenes and tumor suppress genes through miRNA profiling according to the reports mainly in the recent 5 years, providing the evidence of efficient target therapy and effective pro-diagnosis focusing on miRNAs expression of breast cancer patients.     

Role of miR-10b in breast cancer metastasis

Ninety percent of cancer-related mortality is caused by metastasis. Current cancer treatments can control many primary tumors but rarely stop the metastatic spread. Accumulating evidence demonstrates that miRNAs are involved in cancer initiation and progression. Furthermore, several miRNAs have been found to regulate metastasis. In particular, recent studies provide the first functional evidence that overexpression of a specific miRNA, miR-10b, can contribute to the development of metastasis, which can be exploited therapeutically in treating breast cancer metastasis in mice. Further in-depth analysis should provide more precise evaluation of the roles, mechanisms, and therapeutic utility of this miRNA in breast cancer.     

The role of HER2, EGFR,and other receptor tyrosine kinases in breast cancer

Breast cancer affects approximately 1 in 8 women, and it is estimated that over 246,660 women in the USA will be diagnosed with breast cancer in 2016. Breast cancer mortality has decline over the last two decades due to early detection and improved treatment. Over the last few years, there is mounting evidence to demonstrate the prominent role of receptor tyrosine kinases (RTKs) in tumor initiation and progression, and targeted therapies against the RTKs have been developed, evaluated in clinical trials, and approved for many cancer types, including breast cancer. However, not all breast cancers are the same as evidenced by the multiple subtypes of the disease, with some more aggressive than others, showing differential treatment response to different types of drugs. Moreover, in addition to canonical signaling from the cell surface, many RTKs can be trafficked to various subcellular compartments, e.g., the multivesicular body and nucleus, where they carry out critical cellular functions, such as cell proliferation, DNA replication and repair, and therapeutic resistance. In this review, we provide a brief summary on the role of a selected number of RTKs in breast cancer and describe some mechanisms of resistance to targeted therapies.     

Role of miRNAs in breast cancer

miRNAs belong to an important class of endogenous molecules which are present in a wide range of organisms including animals, plants and viruses. They are involved in regulating expression of several genes inside a cell due to presence of complementary region against specific mRNA molecules. Altered expression patterns cause progression of multiple diseases inside an organism. They have also been confirmed to be involved in different cancers including breast cancer. In this review, we discuss role of miRNAs with respect to uncontrolled division of cells, promotion, progression and metastasis in breast cancer.     

MicroRNAs as prognostic indicators and therapeutic targets: potential effect on breast cancer management.

The discovery of microRNAs (miRNA) as novel modulators of gene expression has resulted in a rapidly expanding repertoire of molecules in this family, as reflected in the concomitant expansion of scientific literature. MiRNAs are a category of naturally occurring RNA molecules that play important regulatory roles in plants and animals by targeting mRNAs for cleavage or translational repression. Characteristically, miRNAs are noncoding, single-stranded short (18-22 nucleotides) RNAs, features which possibly explain why they had not been intensively investigated until recently. Accumulating experimental evidence indicates that miRNAs play a pivotal role in many cellular functions via the regulation of gene expression. Furthermore, their dysregulation and/or mutation has been shown in carcinogenesis. We provide a brief review of miRNA biogenesis and discuss the technical challenges of modifying experimental techniques to facilitate the identification and characterization of these small RNAs. MiRNA function and their involvement in malignancy, particularly their putative role as oncogenes or tumor suppressors is also discussed, with a specific emphasis on breast cancer. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment.     

HITS-CLIP reveals key regulators of nuclear receptor signaling in breast cancer

miRNAs regulate the expression of genes in both normal physiology and disease. While miRNAs have been demonstrated to play a pivotal role in aspects of cancer biology, these reports have generally focused on the regulation of single genes. Such single-gene approaches have significant limitations, relying on miRNA expression levels and heuristic predictions of mRNA-binding sites. This results in only circumstantial evidence of miRNA–target interaction and typically leads to large numbers of false positive predictions. Here, we used a genome-wide approach (high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation, HITS-CLIP) to define direct miRNA–mRNA interactions in three breast cancer subtypes (estrogen receptor positive, Her2 amplified, and triple negative). Focusing on steroid receptor signaling, we identified two novel regulators of the ER pathway (miR-9-5p and miR-193a/b-3p), which together target multiple genes involved in ER signaling. Moreover, this approach enabled the definition of miR-9-5p as a global regulator of steroid receptor signaling in breast cancer. We show that miRNA targets and networks defined by HITS-CLIP under physiologic conditions are predictive of patient outcomes and provide global insight into miRNA regulation in breast cancer.     

MicroRNA在三阴性乳腺癌发生发展中的作用

microRNA（miRNA）是近年来发现的一种可以调控基因表达的单链小分子RNA,其表达异常或突变被认为与多种肿瘤的发生、发展有关。有研究表明,miRNA在三阴性乳腺癌中扮演着重要角色,这将为后者的治疗提供新思路。本文就miRNA作为一种新的分子标志物在三阴性乳腺癌中的研究进展作一综述。【关键词】miRNA;三阴性乳腺癌;分子标志物     

Addressing frailty in patients with breast cancer: A review of the literature

Various studies have documented variation in the management of older patients with breast cancer, and some of this variation stems from different approaches to balancing the expected benefit of different treatments, with the ability of patients to tolerate them. Frailty is an emerging concept that can help to make clinical decisions for older patients more consistent, not least by providing a measure of ‘biological’ ageing. This would reduce reliance on ‘chronological’ age, which is not a reliable guide for decisions on the appropriate breast cancer care for older patients.This article examines the potential of frailty assessment to inform on breast cancer treatments. Overall, the current evidence highlights various benefits from implementing comprehensive geriatric assessment and screening for frailty in breast cancer patients. This includes a role in supporting the selection of appropriate therapies and improving physical fitness prior to treatment. However, there are challenges in implementing routine frailty assessments in a breast cancer service. Studies have used a diverse array of frailty assessment instruments, which hampers the generalisability of research findings. Consequently, a number of issues need to be addressed to clearly establish the optimal timing of frailty assessment and the role of geriatric medicine specialists in the breast cancer care pathway.     

Exosome‐encapsulated microRNAs as circulating biomarkers for breast cancer

Breast cancer is a highly prevalent disease, accounting for 29% of invasive cancers in women. Survival from this disease depends on the stage at diagnosis, with patients who are detected earlier having more favourable outcomes. It is because of this that research groups are focusing on the development of a blood‐based biomarker for breast cancer. Such biomarkers may facilitate the detection of breast cancer in its infancy before it has spread beyond the primary site. MicroRNAs (miRNAs) have shown immense potential in this setting. These short, non‐coding RNA sequences have been shown to be dysregulated in breast cancer. Despite showing immense promise, miRNAs have not been successfully implemented in the clinical setting due to a lack of a standardised approach which has resulted in conflicting results. These challenges may be addressed at least in part through the study of exosomes. The biomarker potential for exosomes holds huge promise and may revolutionise the way in which we diagnose and manage breast cancer. These nanovesicles may be isolated from a variety of bodily fluids, including serum, and their miRNA content has been shown to reflect that of the parent breast cancer cell. This review will highlight the nomenclature and defining characteristics of exosomes, and current methods of isolation of serum‐derived exosomes. Initial promising reports on the potential utility of exosomal miRNAs to be used as breast cancer biomarkers will also be addressed.     

microRNA在乳腺癌诊断及预后判断中的作用

乳腺癌是全球女性患病率最高的恶性肿瘤,严重危害广大女性的健康。微小RNA(microRNA,miRNA)是一类小的内源性非编码RNA,通过与mRNA 3’端非翻译区部分互补配对,在翻译后水平调节靶基因的表达。miRNA在乳腺的发育过程中发挥多种作用,其表达异常可能导致乳腺癌的发生。乳腺癌中miRNA的异常表达,以及miRNA在血清中的稳定存在,使miRNA有望成为新的生物标志物用于乳腺癌的诊断及预后判断。     

Epigenetic Therapy in Breast Cancer

Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Epigenetics is defined as reversible changes in gene expression, not accompanied by alteration in gene sequence. DNA methylation, histone modification, and nucleosome remodeling are the major epigenetic changes that are dysregulated in breast cancer. Several genes involved in proliferation, anti-apoptosis, invasion, and metastasis have been shown to undergo epigenetic changes in breast cancer. Because epigenetic changes are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding effective therapies that target these changes. Both demethylating agents and the histone deacetylase inhibitors (HDACi) are under investigation as single agents or in combination with other systemic therapies in the treatment of breast cancer. In this review, we discuss the role of epigenetic regulation in breast cancer, in particular focusing on the clinical trials using therapies that modulate epigenetic mechanisms.     

The role of chemotherapy and targeted agents in patients with metastatic breast cancer

Metastatic breast cancer has always been a challenging disease to treat, with cytotoxic chemotherapy often being deemed a merely palliative treatment that is given to relieve cancer-related symptoms. However with the introduction of more effective systemic therapies over the last two decades, recently we have witnessed substantial improvements in clinical outcomes such that many patients now live with metastatic secondary breast cancer for many years. Various different cytotoxics are used in clinical practice, and targeted biological therapeutics have an increasing role to play in the management of different breast cancer subtypes. The appropriate use of these different systemic therapeutics has been one of the principal reasons for the continued improvement in clinical outcomes for women with advanced breast cancer, including a probable substantial impact on overall survival.     

MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer

Tumor recurrence and metastasis result in an unfavorable prognosis for cancer patients. Recent studies have suggested that specific microRNAs (miRNAs) may play important roles in the development of cancer cells. However, prognostic markers and the outcome prediction of the miRNA signature in breast cancer patients have not been comprehensively assessed. The aim of this study was to identify miRNA biomarkers relating to clinicopathological features and outcome of breast cancer. A miRNA microarray analysis was performed on breast tumors of different lymph node metastasis status and with different progression signatures, indicated by overexpression of cyclin D1 and β-catenin genes, to identify miRNAs showing a significant difference in expression. The functional interaction between the candidate miRNA, miR-30a, and the target gene, Vim, which codes for vimentin, a protein involved in epithelial-mesenchymal transition, was examined using the luciferase reporter assay, western blotting, and migration and invasion assays. The association between the decreased miR-30a levels and breast cancer progression was examined in a survival analysis. miR-30a negatively regulated vimentin expression by binding to the 3'-untranslated region of Vim. Overexpression of miR-30a suppressed the migration and invasiveness phenotypes of breast cancer cell lines. Moreover, reduced tumor expression of miR-30a in breast cancer patients was associated with an unfavorable outcome, including late tumor stage, lymph node metastasis, and worse progression (mortality and recurrence) (p < 0.05). In conclusion, these findings suggest a role for miR-30a in inhibiting breast tumor invasiveness and metastasis. The finding that miR-30a downmodulates vimentin expression might provide a therapeutic target for the treatment of breast cancer.     

Cannabinoids: A new hope for breast cancer therapy?

Breast cancer is a very common disease that affects approximately 1 in 10 women at some point in their lives. Importantly, breast cancer cannot be considered a single disease as it is characterized by distinct pathological and molecular subtypes that are treated with different therapies and have diverse clinical outcomes. Although some highly successful treatments have been developed, certain breast tumors are resistant to conventional therapies and a considerable number of them relapse. Therefore, new strategies are urgently needed, and the challenge for the future will most likely be the development of individualized therapies that specifically target each patient's tumor. Experimental evidence accumulated during the last decade supports that cannabinoids, the active components of Cannabis sativa and their derivatives, possess anticancer activity. Thus, these compounds exert anti-proliferative, pro-apoptotic, anti-migratory and anti-invasive actions in a wide spectrum of cancer cells in culture. Moreover, tumor growth, angiogenesis and metastasis are hampered by cannabinoids in xenograft-based and genetically-engineered mouse models of cancer. This review summarizes our current knowledge on the anti-tumor potential of cannabinoids in breast cancer, which suggests that cannabinoid-based medicines may be useful for the treatment of most breast tumor subtypes.