Exosomal miRNAs in Breast Cancer: Comparison
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MiRNAs are a group of noncoding ribonucleic acid (RNA) with 20–25 nucleotides which always regulate the post-transcriptional level of gene expression negatively. It has been well recognized that miRNAs are involved in the diagnosis, initiation, progression, prognosis, and response to treatment of breast cancer. Compared with free ones, the exosomal miRNAs are more stable since the phospholipid bilayer surrounding exosomes can protect them from being degraded by nuclease in the body fluids.

  • exosome
  • miRNAs
  • breast cancer
  • diagnosis
  • potential biomarkers

1. Introduction

Breast cancer has been the most commonly diagnosed cancer worldwide, with an estimated 2.3 million new cases (11.7%) in 2020. It is also one of the leading causes of cancer death with a mortality rate of 6.9% [1,2][1][2]. Several genetic and environmental risk factors have been proved to favor breast cancer development [3,4[3][4][5][6],5,6], however, the exact cause of breast cancer still remains unclear. The five-year survival rates of breast cancer patients are decreased with the malignant degree of the tumor, with more than 95% for localized breast cancer and less than 25% after metastasis [7]. Early diagnosis and the control of tumor procession are of great importance for the mortality of breast cancer patients. Biomedical imaging combined with tissue biopsy remains the most widely used method for detecting breast cancer [8], despite the fact that it can only detect breast cancer with obvious focus. Liquid biopsy including exosomes [9], circulating tumor cells (CTCs) [10], and circulating tumor deoxyribonucleic acids (ctDNAs) [11] has been recently proposed as a promising diagnosis method in oncology because it is less invasive and can be detected in the early stage of breast cancer without obvious focus.

Exosomes are nanoscale extracellular vesicles released by all cells of prokaryotes and eukaryotes [12]. They inherit many constituents from their donor cells, including proteins [13[13][14],14], lipids, nucleic acids [15], and metabolites, which play important roles in the transmission of messages and exchange of substances among cells [16]. Emerging evidence shows that exosomes can affect the physiological status of cells and have significant effects on adaptive immunity, inflammatory processes, and tumorigenesis processes through transfer micro-ribonucleic acids (miRNAs) [17,18,19][17][18][19]. MiRNAs are a group of noncoding ribonucleic acid (RNA) with 20–25 nucleotides which always regulate the post-transcriptional level of gene expression negatively [20]. It has been well recognized that miRNAs are involved in the diagnosis, initiation, progression, prognosis, and response to treatment of breast cancer [21,22][21][22]. Compared with free ones, the exosomal miRNAs are more stable since the phospholipid bilayer surrounding exosomes can protect them from being degraded by nuclease in the body fluids [23,24][23][24].

2. Exosomal miRNAs in Breast Cancer Progression

Breast cancer stem cells are a subtype of cancer cells with stem-like characteristics. Their development is closely related to the successful metastasis cascade of cancer cells. Cancer-associated fibroblast exosomes with low miR-7641 can promote the stemness of breast cancer cells through HIF-1 alpha [53][25]. Exosomal miR-130a-3p has been reported to inhibit migration and invasion by regulating RAB5B in human breast cancer stem-like cells [56][26]. In addition, tumor-associated macrophages can also promote the invasion of breast cancer through the exosomes secreted by macrophages, which can transfer carcinogenic miRNAs into breast cancer cells [57,58][27][28].

TME also contains a large number of immune cells, including lymphocytes, dendritic cells, monocytes/macrophages, granulocytes and hypertrophic cells, which involve or relate to immune responses. In breast cancer, exosomal miRNAs also participate in the communication between cancer cells and immune cells, thus, regulating adaptive immunity [59][29]. Breast cancer cells can escape the detection of the immune system through exosome-mediated secretions of proinflammatory cytokines from macrophages and decreases in the cytotoxicity of NK and T-cells.

The current death rate of breast cancer has decreased due to improved early monitoring and advanced treatment strategies. Treatment strategies for breast cancer usually combine surgeries with a variety of adjuvant treatments, such as radiotherapy, chemotherapy, targeted therapy, hormone therapy, or a combination thereof. Nevertheless, resistance to therapeutic drugs remains a big obstacle to the success of systematic treatments [63][30]. The drug resistance of breast cancer cells arises from different mechanisms, among which the drug resistance mediated by exosomal miRNAs has attracted much attention. Emerging evidence reveals that the up-regulation/down-regulation of miRNAs can induce the drug resistance of breast cancer cells through various signal pathways [7,64,65][7][31][32].

In addition, some upstream factors which affect miRNAs have also been reported. For example, it has been found that β-elemene can regulate the expression of multidrug resistance specific miRNAs in cells, thereby affecting the content of exosomes, reducing the drug resistance through exosomes, and reversing the drug resistance of breast cancer cells [77][33]. D Rhamnose β-hederin, which could decrease the formation and release of exosomes and reduce the expressions of the most abundant miRNAs (miR-16, miR-23a, miR-24, miR-26a, and miR-27a) in docetaxel-resistant related exosomes, has been used to reverse the chemoresistance of breast cancer cells by regulating the resistance transmission mediated by exosomes [78][34]. Exosomal miRNAs may be considered as excellent biomarkers for the determination of specific drug resistance in breast cancer therapy and regulating miRNAs in exosomes may help us reduce the resistance of breast cancer cells.

3. Exosomal miRNAs in Breast Cancer Diagnosis

Compared to free miRNAs in whole blood or serum, miRNAs in exosomes are more stable and reliable since the phospholipid bilayer surrounding exosomes can protect them from being degraded by nuclease in the body fluids. Therefore, exosomal miRNAs have been a promising biomarker for breast cancer diagnosis and attached more and more attention.

Multiple miRNAs have been identified for breast cancer diagnosis, even for distinguishing breast cancer subtypes [84,101][35][36]. For example, miR-423-5p [102][37], miR-18a-3p [99][38], miR-101, miR-372 [103][39], and eight miRNAs of miR-106a-363 cluster [104][40] which are associated with cancer proliferation, migration, and cell properties, can distinguish breast cancer patients with healthy ones. Other miRNAs, such as miR-373, are higher in triple-negative patients than that in luminal cancer patients or healthy controls; miR-223-3p [105][41], is higher in invasive ductal carcinoma patients than that in diagnosed preoperatively with ductal carcinoma in situ; and miR-93 [106][42], is also upregulated in ductal carcinoma in situ.

RT-qPCR has been widely used in the detection of breast cancer-related miRNAs. Li et al. [118][43] used RT-qPCR to screen candidate miRNAs for breast cancer detection. They profiled miRNA expression in plasma-derived exosome samples from 32 breast cancer patients and 32 normal controls and found miR-122-5p was significantly up-regulated in the plasma-derived exosome of breast cancer patients. Chen et al. [119][44] used 24 serum samples from clinical breast cancer and breast fibroma patients and found miR-18a-3p might have the potential to be a new biomarker to distinguish breast cancer from breast fibroma by using miRNA sequencing combing with RT-qPCR. In addition to screening the potential biomarkers, RT-qPCR can also help to explore the functions of exosomal miRNAs in the process of breast cancer. Zhao et al. [37][45] verified exosomal miRNA-205 might promote drug resistance and tumorigenesis in breast cancer with the help of RT-qPCR. The source of exosomes in this article was a human breast cancer cell line. Sueta et al. [109][46] compared miRNAs derived from exosome between breast cancer patients with recurrence ( n = 16) and without recurrence ( n = 16) by miRNA PCR array and identified four miRNAs (miR-340-5p, miR-17-5p, miR-130a-3p, and miR-93-5p) which were significantly associated with recurrence of breast cancer. In general, RT-qPCR is one of the major methods for exosome identification. It can quantify miRNAs accurately, but it can only detect miRNAs with known sequences.

In breast cancer, miRNA sequencing is often used to screen biomarkers for breast cancer diagnosis and treatment. Wu et al. [121][47] used miRNA sequencing to identify three healthy controls and 27 breast cancer patients and these cases were followed up for two years. They found 54 differentially expressed miRNAs that could distinguish triple-negative breast cancer patients with healthy controls and 3 miRNAs which could assess the risk of recurrence of breast cancer. Zhang et al. [122][48] isolated plasma-derived exosomes from seven post-chemotherapy patients and discovered miR-1-3p might be associated with anthracycline-induced liver injury during the chemotherapy for breast cancer patients with the help of miRNA sequencing. Despite their high price and cumbersome operation steps, miRNAs sequencing plays an irreplaceable role in the study of breast cancer exosomal miRNAs, especially in the search of disease mechanisms and new biomarkers for breast cancer diagnosis and subtypes distinguishment. With the abundance of the sequencing library, breast cancer-related exosomal miRNAs database can be established and new sequencing samples can be classified with the help of artificial intelligence [123][49].

4. Conclusions

There is growing evidence to support the emerging role of exosomal miRNAs in tumorigenesis, proliferation, metastasis, and drug resistance. The identification of breast cancer-specific exosomal miRNAs and their potential mechanism will help early diagnosis of disease, determine the sensitivity to therapeutic drugs, and formulate appropriate treatment strategies. In addition, the breast cancer process can be controlled by regulating specific miRNAs through exosomes. For example, Samaneh et al. [131][50] used mesenchymal stem cell-derived exosomes to deliver miR-381-3p to inhibit triple-negative breast cancer aggressiveness; Ohno et al. [132][51] injected exosomal let-7a to breast cancer tissue for anti-tumor; and Kim et al. [133][52] used let7c-5p for breast cancer therapy. Exosomal miRNAs therapy will be a new strategy for breast cancer treatment. Besides, some techniques, such as molecular beacons, next-generation sequencing, microarrays, and miRNA enzyme immunoassay have made the detection of breast cancer based on miRNAs possible.

However, there are still have some difficulties in exosomal miRNAs applications in clinical. Establishing standards is one of the major limitations in exosomal miRNAs-based breast cancer diagnosis. Most of the existing methods are based on small numbers of samples and miRNAs are detected using different methods. Although in these articles, breast cancer and health groups can be well-differentiated, there is no clear numerical range to identify breast cancer. It is very necessary to test a large number of samples and establish standard test methods. Specificity is another limitation for exosomal miRNAs application in breast cancer. Many miRNAs reported now are not breast cancer-specific, such as miR-21. Combining multiple means and detecting multiple miRNAs at one time are expected to improve the detection accuracy. In conclusion, exosomal miRNAs play an important role in breast cancer progressions and may further be considered as an excellent biomarker for the prevention, early diagnosis, and treatment of breast cancer in the near future.

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