Triple negative breast cancer in the era of miRNA

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Abstract

The objective of this review is to elucidate the role of miRNAs in triple negative breast cancer (TNBC). To achieve our goal, we searched databases such as PubMed, ScienceDirect, Springer, Web of Science and Scopus. We retrieved up to 1233 articles, based a rigorous selection criterion, only 197 articles were extensively reviewed. We selected articles only addressing TNBC, but not other types of breast cancer, with the employed approach being miRNA analysis and/or profiling. Our extensive review resulted in grouping of miRNAs into categories in which specific members of miRNAs have roles in specific mechanism in TNBC i.e., carcinogenesis, invasion, metastasis, apoptosis, diagnosis, prognosis, and treatment. TNBC is an aggressive subtype of breast cancer; therefore, different approaches for accurate diagnosis, prognosis and treatment are needed. In this review we summarize the up-to-date miRNA profiling, prognostic, and therapeutic findings that add to the route of controlling TNBC.

Introduction

Breast cancer (BC) is the most common neoplasm to affect women, with ∼62,930 new breast carcinoma diagnoses expected in the USA alone by the end of 2019 (Siegel et al., 2019). BC is also the second most common cause of cancer-related death among females worldwide, responsible for ∼14 % of all cancer deaths worldwide (Taheripanah et al., 2018). Triple negative breast cancer (TNBC) is a distinct heterogeneous, invasive, clinical BC subtype that accounts for 10–20 % of all BC cases (Synnott et al., 2018); it can occur in young women, where it is characterized by larger tumor sizes and higher tumor grades (Liu et al., 2018a). TNBC is estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor 2 (HER2)-negative, with a diverse molecular profile and an aggressive nature (Sporikova et al., 2018). Specifically, TNBC cells can colonize the lungs, brain and in some cases, bone, to form secondary BC, which carries a poor prognosis (Avery-Kiejda et al., 2017).

To date, the FDA (US Food and Drug Administration) and EMA (European Medicines Agency) have not approved a reliable therapy for TNBC (Karaayvaz et al., 2018). Unfortunately, therapeutic options such as monoclonal antibody and hormonal (e.g. HER2-targeted) therapies, are ineffective in TNBC (Wang et al., 2018). In addition, some patients show poorer outcomes after chemotherapy than patients with other BC subtypes (Kahraman et al., 2018). The short disease-free survival (DFS) and overall survival (OS) times of patients with TNBC, however, calls for the urgent identification of new molecular targets that may improve prognostication or be developed into efficient and specific therapies (Bosch et al., 2009).

MicroRNAs (miRNAs) are one such molecular target to explore in the context of TNBC. miRNAs are small (18–24 nucleotides) noncoding RNAs that are transcribed in a tissue-specific manner to regulate target genes (Cantini et al., 2019). miRNAs have crucial roles in various cellular processes, including cell survival, apoptosis, aging, differentiation, carcinogenesis and metastasis (Wang, 2018). Several miRNAs are up-regulated or down-regulated in different cancer types.

Intensive research efforts have deduced that miRNAs have a dual function in cancer, particularly in TNBC, as tumor suppressors or oncogenes (oncomiRs). As such, miRNAs are considered promising targets for several cancer types, including TNBC (de Brot et al., 2018). Furthermore, differential miRNA expression in TNBC could serve as a reliable biomarker to help predict therapeutic selectivity and efficacy (Liang et al., 2017). Although the data thus far are somewhat controversial, it seems that miRNAs are a major molecular factor involved in several human diseases, including BC and, more precisely, TNBC (Adams et al., 2016). In the following sections, we describe how miRNAs are involved in the diagnosis, prognosis, and treatment of TNBC.

The use of immune checkpoint inhibitor therapies targeting such as Programmed cell death ligand1 (PD-L1) becomes common in treating different types of cancers including TNBC (Gonzalez-Ericsson et al., 2020). Several reports indicated that the anti-PD-L1 antibody combined with auranofin (AF) impaired the growth of 4T1.2 primary tumors (Raninga et al., 2020).

More recently, three newly emerged targeted therapies for TNBC have been approved, including BRCA mutation associated breast cancer (gBRCAm-BC) (aka talazoparib), PARP inhibitors Olaparib and atezolizumab. These therapies are used in combination with nab-paclitaxel for PD-L1+ advanced TNBC (Lyons, 2019).

PARP inhibitors are considered as a potential tool to treat TNBC in combination with cytotoxic therapy or radiotherapy, particularly in the PD-L1+ tumors (Bergin and Loi, 2019). Deregulation of RAD51C, ATM, PALB2, and TP53 occurs upon PARPi treatment can be used as predictive and prognostic tool for the successfulness of the therapy (Geenen et al., 2018).

PARP also can be combined with MYC-regulated homologous recombination to formulate an effective synthetic lethality in TNBC (Carey et al., 2018). This combination of immunotherapy and PARPi may expand their clinical utility in treating TNBC (Wang et al., 2018).

Section snippets

miRNA biogenesis

miRNAs are non-coding RNAs transcribed from either intragenic or intergenic loci, within regions referred to as “gene deserts” (Kinoshita et al., 2018). miRNAs post-transcriptionally regulate gene expression — either the gene from which it originates or remote genes that might be located on a different chromosome (Shirafkan et al., 2018). Lin-14 was the first miRNA to be identified, originally discovered in 1993 in Caenorhabditis elegans, and paved the way to identifying a new mechanism of

Epigenetic changes and miRNA dysregulation in TNBC

Epigenetic changes, such as histone acetylation and DNA methylation, have key roles in the initiation and progression of many types of breast cancer, including TNBC (Mekala et al., 2018). Epigenetics is a fast-growing field of research in which very complicated biological phenomena have become interpretable. Pushing this knowledge to its border might help translate the function of epigenetic markers into clinical practice (Kagara et al., 2012).

miRNAs exhibit a bidirectional relationship with

Oncogenic and tumor-suppressive roles of miRNAs in TNBC

miRNA involvement in cancer was first reported in chronic lymphocytic leukemia, where a critical region on chromosome 13 (specifically, 13q14) was found to contain no tumor suppressor gene but two miRNAs — miR-15a and miR16-a — expressed from the same polycistronic RNA (Calin et al., 2004). miRNA dysregulation has been reported in almost all cancers and can have consequences on all stages of carcinogenesis (Wang, 2018). miRNA expression can be modulated via different mechanisms, such as by

miRNA contribution to TNBC metastasis

Most deaths related to TNBC are due to secondary tumors (Liu et al., 2018b). Tumor metastasis is a complex process and perhaps the least-well understood event in the arena of cancer biology (Lambert et al., 2017). Mechanistically, metastasis is sustained by a wide array of related genes and miRNAs known as metastamiRs (Hurst et al., 2009). These metastamiRs are involved in TNBC tumor initiation and regulate crucial steps in metastasis, including EMT, apoptosis and angiogenesis (Piasecka et al.,

AngiomiRs regulate angiogenesis in TNBC

Angiogenesis is a tightly regulated physiological process by which new blood vessels develop from already existed ones (Zhao and Adjei, 2015). In developing cancer, endothelial cells are active upon releasing of epidermal growth factor (EGF), estrogen, IL-8, prostaglandin E1 and E2, TNF-α, and VEGF, and other factors that enhance cell motility (Rajabi and Mousa, 2017). Angiogenesis is controlled by several genes (Schneider et al., 2008) and regulated post-transcriptionally by a class of miRNAs

Diagnostic value

A plethora of studies have attempted to develop reliable diagnostic tools to differentiate the molecular subtypes of TNBC; thus far, only miRNAs have proved to form the basis of a successful diagnostic tool (Sun and Gribskov, 2018). Various studies suggested that the expression profile of different miRNAs could distinguish breast cancer specimens from that normal tissues (Tang et al., 2019) and the TNBC from other clinical breast cancer subtypes (Jin et al., 2016).

Circulating miRNAs have become

Chemoresistance-associated miRNAs

Chemoresistance is one of the main causes of therapeutic failure in TNBC patients (Han et al., 2019), although the underlying mechanisms are not fully understood (Xiong et al., 2018). Indeed, several miRNAs are associated with drug resistance in TNBC (Bach et al., 2017). A study conducted TNBC is not susceptible to hormone inhibition and must therefore be treated with neoadjuvant chemotherapy, but unfortunately, patients develop resistance to this intervention, which makes it difficult to fully

Future directions

Developing therapeutic strategies based solely on miRNAs has potential in cancer treatment as we already have a deep understanding of the mechanisms and pathways controlling miRNA–mRNA interactions. This understanding facilitates the development of new classes of cancer therapeutic drugs that target only specific miRNA(s). Indeed, we now know that miRNA dysregulation can disrupt gene expression and initiate tumors; thus, targeting these malfunctioning miRNAs has the potential to revert affected

Limitations of using miRNA as biomarker in TNBC

One of the main limitations of using miRNA in TNBC is the formulation of reliable panel of miRNA for early prediction, diagnosis, or treatment of TNBC (Witwer, 2015). Low abundance of miRNA in blood stream also impedes their detection using the standard profiling tools. However, several methods have been proposed to tackle this problem, such as isolating miRNA an enrich it before expression profiling (Hamam et al., 2016). Furthermore, using serum samples rather than plasma samples gives more

Conclusions

TNBC is a heterogeneous, aggressive BC subtype that requires different approaches for both diagnosis and treatment than luminal subtypes. Over the past two decades, a plethora of reports have indicated that several miRNAs or miRNA clusters are involved in TNBC carcinogenesis, where they might serve as oncogenes (oncomiRs) or tumor suppressors. Furthermore, miRNAs are associated not only with tumor initiation but also with progression and metastasis and are thus a valid target for precision

Funding

The authors receive no fund for this work.

Declaration of Competing Interest

The authors report no declarations of interest.

Hussein Sabit, PhD, is Professor of Cancer Genetics, at Institute of Research and Medical Consultation (IRMC) of Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia. I received my PhD in 2007 (Molecular Genetics) from Ain Shams University, Egypt. I have been working on molecular mechanisms controlling cancer progression and metastasis. I mam currently involved in several research projects related to cancer Epigenetics between KSA, Egypt and Spain. I have also a strong record of

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  • Cited by (0)

    Hussein Sabit, PhD, is Professor of Cancer Genetics, at Institute of Research and Medical Consultation (IRMC) of Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia. I received my PhD in 2007 (Molecular Genetics) from Ain Shams University, Egypt. I have been working on molecular mechanisms controlling cancer progression and metastasis. I mam currently involved in several research projects related to cancer Epigenetics between KSA, Egypt and Spain. I have also a strong record of teaching experience for 22 years. I have nearly 61 publications in the field of Cancer Biology, Genetics, and Epigenetics. I am supervising 28 Master and PhD thesis in KSA and Egypt.

    Emre Cevik, PhD, Assistant professor of Biochemistry at Institute of Research and Medical Consultation (IRMC) of Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia. I got my PhD in 2016 from Istanbul University, Department of Biotechnology, Turkey. I have 65 publications in different fields of Biotechnics and chemistry. I completed my PhD in the field of electrochemistry, Biosensor applications for the detection of cancer biomarkers. My current research focuses on the design, development, and manufacture of screen-printed electrode-based compact biosensors for the detection of multiple cancer biomarkers.

    Huseyin Tombuloglu, PhD, is Associate Professor at Institute of Research and Medical Consultation (IRMC) of Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia. He received his BSc. degree in 2007 from Istanbul University, Department of Molecular Biology and Genetics, Turkey, and also, he studied as an exchange student in University of Groningen, the Netherlands. He obtained MS degree (Biology) in 2010 and PhD degree (Biotechnology) in 2014. He became Assistant Professor in 2014, and Associate Professor in 2018. He has more than 15 years of teaching and research experience in Genetics, Molecular Biology, Plant Genomics, and Biotechnology, as well as Bioinformatics. He is one of the members of the International Olive Genome Sequencing Consortium. Currently, he is one of the research team members of the International Garlic Genome Sequencing Consortium (IGGS) (http://garlicgenome.org/). His current research is focused on genome sequencing of plants, data analysis, proteomics, and nanoparticle-plant interaction.

    Shaimaa Abdel-Ghany, PhD, is Associate Professor of Environmental Biotechnology at the College of Biotechnology, Misr University for Science and Technology, Egypt. I received my PhD in Cancer Genetics in 2010 and worked as Assistant Professor of Genetics at the same College. I have 23 publications in the field of molecular genetics and cancer. I am teaching for 10 years at the same College. I am involved in 3 mega research projects between Egypt and KSA related to Breast Cancer.

    Guzin Tombuloglu, PhD, received her MS degree (Biology) in 2008 and PhD degree (Biotechnology) in 2014. She has experience in transcriptome sequencing, plant abiotic stress tolerance, molecular biology of plants. During her PhD, she studied transcriptomics identification of boron tolerance mechanism in barley. She has experienced several projects on abiotic stress, plant stress responses, Boron toxicity and transcriptomics. She has given several courses on teaching Genetics, Molecular Biology, and Biotechnology education for more than 15 years. She also worked as a Chairman in Pathology Laboratory Techniques Programme and Assistant Manager at Vocational School of Medical Sciences at the university level.

    Manel Esteller, PhD, MD, (Sant Boi de Llobregat, Barcelona, Catalonia, Spain, 1968) graduated in Medicine from the University of Barcelona in 1992, where he also obtained his pH.D. degree specialising in molecular genetics of endometrial carcinoma, in 1996. He was an Invited Researcher at the School of Biological and Medical Sciences at the University of St. Andrews, (Scotland, UK) during which time his research interests focused on the molecular genetics of inherited breast cancer. From 1997–2001, Esteller was a Postdoctoral Fellow and a Research Associate at the Johns Hopkins University and School of Medicine, (Baltimore, USA) where he studied DNA methylation and human cancer. His work was decisive in establishing promoter hypermethylation of tumor suppressor genes as a common hallmark of all human tumours. From October 2001 to September 2008 Manel Esteller was the Leader of the CNIO Cancer Epigenetics Laboratory, where his principal area of research were the alterations in DNA methylation, histone modifications and chromatin in human cancer. Since October 2008, Dr Esteller is the Director of the Cancer Epigenetics and Biology Program (PEBC) of the Bellvitge Institute for Biomedical Research (IDIBELL) in Barcelona, Chairman of Genetics in the School of Medicine of the University of Barcelona, and an ICREA Research Professor. His current research is devoted to the establishment of the epigenome and epitranscriptome maps of normal and transformed cells, the study of the interactions between epigenetic modifications and non-coding RNAs, and the development of new epigenetic drugs for cancer therapy. Author of 508 original publications in peer-reviewed scientific journals, 24 of them categorized as “Highly Cited Paper” by Thomson Reuters, he is among the most cited researchers in the world (top 1%) with the recognition “Highly Cited Researcher” (decade 2008–2018) by Clarivate Analytics. Dr Esteller has a Total Impact Factor of 4,794.994 and a Total Number of Citations of 61,389, having an h-Index of 120. He is also a Member of numerous international scientific societies, Editorial Boards and reviewer for many journals and funding agencies. Dr Esteller is also Associate Editor for Cancer Research, The Lancet Oncology, Carcinogenesis, Genome Research and The Journal of The National Cancer Institute. He is also Editor-in-Chief of Epigenetics.

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