miRNA as a Therapy Target in Breast Cancer: History
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Contributor:
Iga Dziechciowska
,
Małgorzata Dąbrowska
,
Anna Mizielska
,
Natalia Pyra
,
Natalia Lisiak
,
Przemysław Kopczyński
,
Magdalena Jankowska-Wajda
,
Błażej Rubiś
Most miRNAs are found inside the cell but also migrate in body fluids such as blood, urine, saliva, or breast milk. Thus, these short RNA particles are considered diagnostic and therapeutic markers, especially in cancer, neurology, or cardiology. It is noteworthy that miRNA dysregulation is common in many cancer cases as they can act as both tumor suppressors or oncogenes. miRNA as a therapy target is gaining extensive attention due to its various effects on cancer development. For example, supplementation of miRNA mimics (miR-15a) in prostate cancer cell lines induced apoptosis and blocked cell proliferation. Another study showed that miR-99a reduced breast cancer cell proliferation, invasion, and migration in vitro and in vivo. Numerous studies showed that targeting miRNA with its antagonists might lead to tumor suppression and efficient, personalized cancer therapy. Significantly, miRNA-targeted therapy may influence a single gene and whole cellular pathways, which can be particularly beneficial. Specifically, the latest approach in miRNA therapeutics is mainly based on two strategies, i.e., the inhibition of oncogenic miRNAs and, hence, the restoration of the expression of tumor-suppressing genes that they target, or restoring the expression of tumor-suppressing miRNAs and consequently inhibiting the oncogenes that they target. Downregulation of tumor miRNA suppressors leads to the overexpression of their target oncogenes. To restore the expression of tumor-suppressing miRNAs, promising areas are the mimic miRNAs. They are small, chemically modified (2′-O’methoxy) double-stranded RNA molecules that mimic the endogenous mature miRNA molecules.
  • breast cancer
  • miRNA profiling
  • cancer diagnostics
  • cancer therapy

1. The Role of miRNA in Breast Cancer Chemoresistance

Numerous factors, including late diagnosis or resistance to therapeutic agents, may cause therapy failure in cancer therapy. The two basic types of drug resistance, i.e., innate or acquired, constitute a severe challenge in oncology. Recently, both these mechanisms were reported to be associated with miRNAs that modulate drug-resistance-related genes or affect genes related to cell proliferation, cell cycle, DNA damage repair, and apoptosis [1]. Hence, the miRNA-based therapeutic approach seems to provide an interesting and efficient perspective in cancer therapy. Specifically, in breast cancer, several miRNAs were suggested to play a critical role in therapy response, showing a tumor-type-dependent effect. miR-200c, miR-155, and miR-218 were shown to mediate the therapeutic effect of selected drugs, i.e., (i) trastuzumab, (ii) aclitaxel, VP16, doxorubicin, and (iii) cisplatin, respectively [2]. Another study demonstrated 123 miRNAs that were dysregulated in vinorelbine (NVB)-resistant breast cancer cell lines (MDA-MB-231/NVB). A total of 31 of these miRNAs were downregulated, and 92 were upregulated in those cells, suggesting complex regulation [3]. It was also demonstrated that 17 specific miRNAs were involved in oncogenic pathways, including TGFβ, mTOR, Wnt, and MAPK. It is noteworthy that elevated TGFβ signaling and downregulation of miR-200c were also demonstrated in trastuzumab-resistant breast cancer cells while increased miR-200c or the blockade of TNFβ signaling increased trastuzumab sensitivity and inhibited invasiveness of breast cancer cells [4].
Similarly, miR-494 and miR-141 were shown to suppress the progression of breast cancer by repressing β-catenin expression [5][6]. Recently, Yu et al. reported that the miR-17/20 cluster increased tamoxifen sensitivity and attenuated doxorubicin resistance in MCF-7 cells via Akt1 [7]. Another study showed that miR-218, which targets BRCA1, was downregulated in cisplatin-resistant breast cancer cell lines and, interestingly, the restoration of miR-218-sensitized MCF-7 breast cancer cells to this drug [8]. Numerous studies show other miRNAs that are capable of modifying the response of breast cancer cells to different therapeutic agents, including 5-fluorouracil, trastuzumab, lapatinib, cisplatin, fulvestrant, tamoxifen, paclitaxel, doxorubicin, and palbociclib. The most commonly reported BC-related miRNAs (and probably the most critical ones) are presented in Table 1. Recent data suggest that the function of some miRNAs may be involved in the epithelial–mesenchymal transition process that mediates multidrug resistance (MDR) phenotype promotion. A thoroughly revised contribution of miRNAs to individual ABC family transporters was shown elsewhere [9]. Thus, further screening and miRNA profiling in cancer tissues is highly required as it may provide in-depth information regarding critical genes expression regulation. It may be, however, that similarly to wide-genome sequencing that aims to evaluate the role of individual SNPs in genomic DNA, miRNA profiling will not be sufficient to evaluate the risk or monitor disease progression and therapy efficacy. The only possible way seems to be the further assessment of clinical samples that show real mechanistic networks in vivo. Importantly, some clinical trials are being carried out—more than 50 refer to miRNA application in breast cancer [10].
Table 1. The list of critical miRNAs associated with breast cancer (according to [11], modified) reported as good diagnostic or therapeutic candidates. The candidates were selected based on the latest reports indicating the role of miRNA in breast cancer. Consequently, a broad analysis of selected miRNA targets suggested some good candidate markers based on the global data at TargetScanHuman 8.0 [12].
miRNA Regulation in Breast Cancer Cells Source and Detection Method Target Target Effects/Action Metabolic Consequences
miR-21 Upregulated Serum, qRT-PCR [13] PTEN [14][15] Downregulation of PTEN expression [14][15][16] Drug resistance to doxorubicin in HER2- BC cells [16]
* miR-21 inhibition induces PTEN expression [17] * Restored trastuzumab sensitivity in the resistant BC xenografts in vivo [17]
PTEN/Akt [18] Downregulation of PTEN expression and Akt activation [18] Induction of EMT and gemcitabine resistance [18]
PI3K/Akt, MEK/ERK [15] Activation PI3K/Akt and MEK/ERK signaling pathways [15] Development of MDR [15]
TPM1, TGF-β [19] Repression of expression TPM1 [20][21] Increased BC cells proliferation, migration, invasion, survival, and EMT [19]
Mesenchymal cell markers (N-cadherin, Vimentin, α-SMA) [22] Activation of mesenchymal cell markers [22] Re-expression of miR-21 is responsible for migration and invasion by activating the EMT process in MCF7 cells [22]
Epithelial cell marker (E-cadherin) [22] Inhibition of epithelial cell marker [22]
miR-106a Upregulated Serum, qRT-PCR [23] Bcl-2,ABCG2, BAX, P53, RUNX3 [24] Upregulation of Bcl-2 protein and multidrug transporter ABCG2. Downregulation of BAX protein and genes products: P53, RUNX3 [24] Promotes BC cells proliferation and invasion [24]
* Inhibition of miR-106a downregulates the expression of Bcl-2, ABCG2 and upregulates the BAX, P53, RUNX3 expression [24]  
RAF-1 [23] Decreases RAF-1 levels and RAF-1 is a part of MAPK/ERK signaling pathway [23] Possibly induces proliferation and decreases apoptosis in BC cells through regulation of the MAPK/ERK signaling pathway, which controls gene expression [23]
ZBTB4 [25][26][27] Negative regulation of ZBTB4 gene, which functions as a tumor suppressor gene [25][26][27] * Restoration of ZBTB4 suppress Sp1, Sp3, Sp4 expression resulting in inhibition of BC cells proliferation, invasion [25][26][27]
miR-155 Upregulated Serum, qRT-PCR [28] TERF1 [29] Reduction in the shelterin component TRF1 expression. TRF1 regulates telomere length and suppresses DNA breakage [29] Antagonization of telomere integrity in BC cells and increased genomic instability [29]
SOCS1 [30] Repression of SOCS1 (negative feedback regulator of JAK/STAT signaling) [30] Constitutive activation of STAT3 in BC cells, promotion of cell proliferation and colony formation [30]
C/EBPβ [31][32] Loss of CCAAT-enhancer binding protein beta (C/EBPβ) [31][32] Modification of TGF-β response; from growth inhibition to EMT, invasion, and metastasis in BC. Promotion of BC progression [31][32]
mir-141 Downregulated Tissue, qRT-PCR, Microarray [33] ANP32E [33] Regulation of ANP32E (positive regulator of tumor growth and metastasis) [33][34] ANP32E induces tumorigenesis of BC by upregulating E2F1 and promoting the G1/S transition [34]
** Overexpression of miR-141 downregulated ANP32E expression [33] ** Inhibition of BC cells proliferation, migration, and invasion [33]
SIP1 [35] Regulation of EMT [35] EMT plays a crucial role in early tumor metastasis and SIP1 is a promoter of cancer progression [35]
let-7c Downregulated Serum, qRT-PCR [36] ERCC6 [37] Upregulation of ERCC6 [37] Intensified cancer growth ability and lower rate of apoptosis; DNA damage accumulation [37]
BCL2, BAX [38] ** Overexpression of let-7c decreases level of Bcl-2 and increases the level of BAX, TP53, PTEN [38] ** Promotion of apoptotic cell death, suppression of cancer progression [38]
ERα and Wnt signaling [39] ** Overexpression of let-7c inhibits estrogen induction in ERα and Wnt signaling [39] ** Inhibition of BCSCs self-renew and suppresses tumor formation [39]
miR-335 Downregulated Serum, qRT-PCR [40] BRCA1 [41][42] Downregulation of BRCA1 [41] Accelerated tumor growth, genomic instability, BC progression [41]
** Overexpression of miR-335 upregulates the level of BRCA1 [41][42] ** Decreased cell viability and increased apoptosis [41][42]
miR-126 Downregulated Tissue, qRT-PCR [43] VEGFA [43], PIK3R2 [44] Inactivation of the PIK3R2/PI3K/Akt/mTOR signaling pathway [44] Vasculogenesis, angiogenesis resulting in tumor growth [43]
Resistance to trastuzumab [44] in SKBR3 and BT747 cell lines
ADAM9 [45] ** Upregulation of miR-126 is silencing ADAM9 gene [45] ** Inhibition of BC cells invasion and metastasis [45]
miR-199a Downregulated Tissue, qRT-PCR [46] PAK4/MEK/ERK signaling pathway [47] Regulation of PAK4/MEK/ERK signaling pathway [47] PAK4 activates the ERK pathway, and MEK/ERK pathway plays a part in PAK4-induced cell growth regulation [47]
** MiR-199a/b-3p downregulates PAK4 expression and PAK4/MEK/ERK signaling pathway [47] ** Suppression of BC cells migration and invasion [47]
miR-101 Downregulated Tissue, qRT-PCR [48] COX-2/MMP1 signaling pathway [49] Upregulation of COX-2/MMP1 signaling pathway [49] Promotes transmigration of metastatic BC cells through the brain endothelium [49]
** Restoring miR-101-3p in BC cells reduces COX-2/MMP1 expression [49] ** Reduction in transmigratory ability [49]
miR-9 Upregulated Cell culture, qRT-PCR [50] FOXO1 [51] Downregulation of FOXO1 expression [51] Promotion of proliferation, migration, and invasion of BC cells [51]
STARD13 [52] Repression of STARD13 [52] Upon stimulation of PDGFRβ signaling, miR-9 could promote the formation of vascular-like structures of TNBC [52]
E-cadherin [51][53] E-cadherin downregulation [53][54] Increased tumor angiogenesis [54]
Primes BC cells to EMT and invasion [53]
* refers to report showing effects of miR inhibition. ** refers to report showing effects of miR activation.
Some translational potential shows the studies that involve a combination of miRNA modulators with anti-cancer chemotherapeutics (specifically, a combination of antagomiRs with therapeutic agents). Alternatively, mimics could be applied that reinforce the function and expression of miRNAs. 

2. The Role of miRNA in Breast Cancer Stem Cells

Some recent studies revealed that both cancer stem-like properties and drug resistance were associated with EMT. As mentioned above, miRNAs play a pivotal role in regulating EMT phenotype. As a result, some miRNAs impact cancer stemness and drug resistance [55], which might show some benefits to clinical treatment. Breast cancer stem cells (BCSCs) show self-renewal and differentiation capacities that contribute to the aggressiveness of metastatic lesions, and all these mechanisms can be controlled by regulatory miRNAs [56]. As demonstrated, the expression of microRNAs can be deregulated in BCSCs [57]. Specifically, mir-21, mir-22, mir-29a, and mir-221/222 were shown to increase tumorigenesis, while miR-34a, miR-628, miRNA-140-5p, and miRNA-4319 were reported to decrease metastasis in BCSCs [31][58][59]. The specific pathways targeted by miRNAs are mediated by the key players in cancer development and proliferation, including HIF-1 alpha, PI3K/Akt, and STAT3 signaling, which play critical roles in the prognosis and survival of BCSCs [56].

3. The Role of miRNA in Cancer Cell Cycle Control

Cell cycle dysregulation is a recognized hallmark of cancer, and its aberrant activation has been related to poor prognosis and drug resistance. Different miRNAs have been described to target genes involved in cell cycle regulation, leading to drug resistance or sensitivity. They were reported not only to target specific pathways but also were shown to be cell cycle step-specific [9].
Several miRNAs have been shown to induce cell cycle arrest due to targeting cyclins. One of them is miR-34a, which was demonstrated to increase resistance to docetaxel (DTX) in luminal BC cells, probably through the inhibition of cyclin D1 (CCND1) and B-cell lymphoma 2 (Bcl-2), inducing G1 arrest and blocking DTX effectiveness as a consequence [60]. miR-93 has also been linked to cell cycle arrest in the G1/S phase. Moreover, some other miRNAs have been shown to modulate drug resistance through targeting CDKs. One of them is miR-29c (targeting directly CDK6), which was downregulated in BC compared to normal tissues [61]. miR-29c overexpression decreased CDK6 level, inducing cell cycle arrest and PTX sensitivity.
Additionally, Citron et al. [62] showed that miR-223 expression levels could predict the effect of CDK4/6 inhibitors and palbociclib (PAB), as well as patients’ prognosis for invasive ductal carcinoma. It was demonstrated that miR-223 was downregulated in luminal and HER2+ BC subtypes. Its low expression was correlated with cell cycle deregulation, poor prognosis, PAB resistance, and low survival in BC patients. Significantly, miRNAs were also shown to affect one of the essential response pathways that are triggered by cancer drugs, i.e., DNA repair pathways, including ATM [63].

4. miRNAs and Cell Death

Sooner or later, applying specific miRNAs in cancer therapy is supposed to provoke cancer cell death. As demonstrated, it can be caused in a particular manner, also due to miRNA involvement. This makes it again a promising strategy to consider, especially since the miRNA-target gene interactions show numerous effects that directly involve cell death modulators. Some examples are miR-125b, which confers resistance to PTX by suppressing the expression of BAK1 [64], miR-149-5p, which was found to be downregulated in PTX-resistant cells and its overexpression demonstrated to increase BAX expression [65], or miR-663b that confers TAM resistance by indirectly upregulating BAX [66]. Additional miRNAs modulate drug response by regulating the expression of Bcl-2 family members [67]. Moreover, miR-203a-3p and miR-203b-3p have been reported to decrease the antiapoptotic protein Bcl-XL and to be correlated to PTX sensitivity in BC positively regulated by MYC in cell line models of PTX-responsive BC [68].
Interestingly, miR-100 was found to be downregulated in BC cell lines with acquired resistance to CIS. In turn, overexpression of miR-100 showed increased sensitivity to CIS due to modulation of the HCLS1-associated protein X-1(HAX-1), an inhibitor of mitochondrial apoptosis that maintains mitochondrial membrane potential in cancer cells [69]. miR-944 inhibitors facilitated CIS-induced loss of mitochondrial membrane potential in resistant models, resulting in intrinsic apoptosis via targeting Bcl-2 interacting protein 3 (BNIP3) [69].
Similarly, miRNAs control critical mediators of apoptosis [70] and autophagy [71] at different levels, including PI3K/Akt/mTOR, ATGs, and LC3 [71]. Primary reports showed some specific miRNAs that affected STAT3 and ATG12 targets [72], while further studies demonstrated broader roles of autophagy-related microRNAs in cancer cells [73], showing numerous miRNAs acting at the levels of induction, nucleation, expansion, fusion, degradation, and recycling. With so many miRNA particles and the dynamics of autophagy, it is difficult to show a specific pattern that would apply to any specific cancer type. However, as miRNAs target specific genes, monitoring their expression during promoting (e.g., rapamycin, everolimus) or inhibiting autophagy (e.g., chloroquine, hydroxychloroquine) may reflect metabolic alterations that accompany different stages of therapy. 

This entry is adapted from the peer-reviewed paper 10.3390/cimb45120595

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