Introduction
Breast cancer and breast cancer heterogeneity
MicroRNAs
Materials and methods
MicroRNAs and breast cancer
The role of microRNAs in breast cancer biology and metastasis
miRNA
|
Target
|
Function
|
Number of samples
a
|
Reference
|
---|---|---|---|---|
miR-10b
| HOXD10 | Promotes cell migration, invasion and metastasis | n = 23 | |
miR-21
| PDCD4, HIF1A | Promotes invasion, metastasis, migration and EMT | Cell culture study | |
TPM1, PTEN, PDCD4 | Promotes invasion | n = 17 | [20] | |
TIMP3 | Promotes invasion | n = 32 | [21] | |
miR-155 | SOCS1 | Promotes cell growth and proliferation | n = 15 | [23] |
TP53INP1 | Promotes proliferation | Cell culture study | [24] | |
FOXO3 | Promotes proliferation and survival | n = 115 | [25] | |
miR-373
| CD44 | Promotes cell migration and invasion | n = 11 | [26] |
Promotes invasion and metastasis | Cell culture study | [27] | ||
miR-520c
| CD44 | Promotes cell migration, invasion and metastasis | n = 11 | [26] |
miRNA
|
Target
|
Function
|
Number of samples
a
|
Reference
|
---|---|---|---|---|
miR-125b
| EPO, EPOR | Inhibits cell proliferation and differentiation | n = 42 | [29] |
ENPEP, CK2-α,CCNJ, MEGF9 | Inhibits cell proliferation | n = 25 | [30] | |
ERBB2 | Inhibits migration and invasion | Cell line study | [31] | |
miR-205 | HMGB3 | Suppresses proliferation and invasion | n = 20 | |
miR-17-92
| Mekk2 | Promotes NK cell antitumoral activity and reduces metastasis | n = 20 | |
miR-206
| Cyclin D2, Cx43 | Reduces migration, invasion and metastasis | n = 128 | |
miR-200
| ZEB1/2, SNAI1/2 | Reduces tumor growth, metastasis and EMT | n = 70 | |
miR-146b
| NFkB, STAT3 | Reduces survival and metastasis | n = 91 | |
miR-126
| IGFBP2, MERTK,PITPNC1 | Reduces metastasis and angiogenesis | n = 117, n = 295 | [43] |
No specific targets listed | Reduces tumorigenesis and metastasis | Cell line study | [44] | |
miR-335
| SOX4, TNC | Suppresses metastasis and migration | n = 20 | |
miR-31
| RhoA | Inhibits several steps of the invasion-metastasis cascade in breast cancer | n = 54 | [46] |
WAVE3, RhoA | Reduces cancer progression and metastasis | Cell line study | [47] | |
WAVE3 | Reduces cancer progression and metastasis | n = 19 | [48] |
Oncogenic microRNAs and ‘metastamiRs’
Tumor-suppressive and metastasis-suppressive microRNAs
Context-dependent microRNAs
MicroRNA detection and normalization
MicroRNA detection and genome-wide approaches
Detection method
|
Throughput
|
Sensitivity
|
Specificity
|
Reference
|
---|---|---|---|---|
Northern blotting | Low | Low | High | [53] |
Microarray | High | Low | Low | [54] |
Bead-based flow cytometry | High | Medium | High | [6] |
qRT-PCR | High | High | High | [55] |
In situ hybridization | Low | Low | Low | [56] |
Next-generation sequencing | High | High | High |
MicroRNA normalization
MicroRNAs as diagnostic, predictive, and prognostic biomarkers
MicroRNAs as diagnostic biomarkers for breast cancer heterogeneity
Early diagnosis of breast cancer
miR signature
|
Expression (BC vs normal)
|
Sample type
|
Number of samples: BC (normal)
|
Validation
|
Reference
|
---|---|---|---|---|---|
miR-15a | Upregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-18a
| Upregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-107 | Upregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-425 | Upregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-133a
| Downregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-139-5p | Downregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-143 | Downregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-145
| Downregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-365 | Downregulated | Serum | n = 48 (24) | n = 60 (51) | [62] |
miR-155 | Upregulated | Serum | n = 184 (75) | Meta-analysis (inclusion of 3 studies)
| [63] |
miR-1 | Upregulated | Serum | n = 32 (22) | n = 132 (101) | [64] |
miR-133a
| Upregulated | Serum | n = 32 (22) | n = 132 (101) | [64] |
miR-133b | Upregulated | Serum | n = 32 (22) | n = 132 (101) | [64] |
miR-92a | Upregulated | Serum | n = 32 (22) | n = 132 (101) | [64] |
miR-148b | Upregulated | Plasma | n = 127 (80) | n = 207 (80) | [65] |
miR-376c | Upregulated | Plasma | n = 127 (80) | n = 207 (80) | [65] |
miR-409-3p | Upregulated | Plasma | n = 127 (80) | n = 207 (80) | [65] |
miR-801 | Upregulated | Plasma | n = 127 (80) | n = 207 (80) | [65] |
miR-16 | Upregulated | Plasma & tissue | n = 15 (15) | n = 170 (100)a
| [66] |
miR-21 | Upregulated | Plasma & tissue | n = 15 (15) | n = 170 (100)a
| [66] |
miR-451 | Upregulated | Plasma & tissue | n = 15 (15) | n = 170 (100)a
| [66] |
miR-145
| Downregulated | Plasma & tissue | n = 15 (15) | n = 170 (100)a
| [66] |
miR-18a
| Overexpressed in cases compared to controlsb
| Serum | n = 205 (205) | n = 5 (5) | [67] |
miR-181a | Overexpressed in cases compared to controlsb
| Serum | n = 205 (205) | n = 5 (5) | [67] |
miR-222 | Overexpressed in cases compared to controlsb
| Serum | n = 205 (205) | n = 5 (5) | [67] |
Breast cancer molecular subtypes and microRNAs
Luminal A
|
Basal
|
HER2
|
Normal-like
|
---|---|---|---|
let-7c | miR-18a | miR-142-3p | miR-145 |
miR-10a | miR-135b | miR-150 | miR-99a |
let-7f | miR-93 | miR-100 | |
miR-155 | miR-130a |
miRNA
|
Median accuracy, percentage
|
Increased miRNA expression gives higher probability of:
|
---|---|---|
ER status | ||
miR-342 | 83.3 | ER (+) status |
miR-299-3p | 100 | ER (−) status |
miR-217 | 100 | ER (+) status |
miR-190 | 100 | ER (−) status |
miR-135b | 100 | ER (-) status |
miR-218 | 100 | ER (+) status |
PR status | ||
miR-520 g | 83.3 | PR (−) status |
miR-377 | 83.3 | PR (+) status |
miR-527-518a | 100 | PR (−) status |
miR-520f-520c | 100 | PR (+) status |
HER2/neu status | ||
miR-520d | 100 | HER2/neu (+) status |
miR-181c | 100 | HER2/neu (−) status |
miR-302c | 100 | Weak response |
miR-376b | 100 | HER2/neu (+) status |
miR-30e-3p | 100 | Weak response |
Breast cancer histological subtypes and microRNAs
Predictive microRNAs
Therapy
|
Generic name
|
miRNA
|
Role in response
a
|
Evidence
|
Number of patients or type of cells
|
Reference
|
---|---|---|---|---|---|---|
Hormone therapy | ||||||
SERM | Tamoxifen | miR-375 | Sensitivity | Preclinical/clinical | 2 BC datasets | [80] |
miR-342 | Sensitivity | Preclinical | MCF-7 | [74] | ||
Sensitivity | Clinical | n = 791 | [81] | |||
miR-221/222 | Resistance | Preclinical | MCF-7, T47D, MM-468 | |||
SERD | Fulvestrant | miR-221/222 | Resistance | Preclinical | MCF-7 | [85] |
AI | Letrozole | let-7f | Sensitivity | Preclinical/clinical | n = 23 | [86] |
Targeted therapy | ||||||
Monoclonal AB | Trastuzumab | miR-210 | Resistance | Preclinical/clinical | n = 43 | [87] |
Chemotherapy | ||||||
FEC | miR-125b | Resistance | Preclinical/clinical | n = 56 | [89] | |
Resistance | Preclinical | MM-435, SKBR3 | [88] | |||
Resistance | Clinical | n = 185 | [90] | |||
Taxol/doxo | miR-30c | Sensitivity | Preclinical | T47D, MCF-7, MM-231 | ||
Taxol | miR-21 | Resistance | Preclinical | MM-468 | ||
Radiotherapy | ||||||
Radiotherapy | miR-34a | Sensitivity | Preclinical | T47D, MCF-7, MM-231 |
MicroRNAs associated with hormone therapies
MicroRNAs associated with targeted therapies
MicroRNAs associated with response to chemotherapeutic agents
MicroRNAs associated with radiotherapy
Prognostic microRNAs
miRNAs associated with positive outcome
| ||||||
---|---|---|---|---|---|---|
miRNA
|
Case cohort
|
Validation cohort
|
Reference
| |||
Detection
|
Cells of origin
|
Number of samples
|
Technique
|
Number of samples
| ||
let-7b | LNA-ISH | Early invasive BC | 1,432 | qRT-PCR | 40 | [97] |
LNA-ISH | Heterogeneous BC | 80 | NR | NR | [101] | |
miR-205 | LNA-ISH | Ductal BC | 1,475 | qRT-PCR | 40 | [97] |
qRT-PCR | Heterogeneous BC | 84 | NR | NR | [102] | |
miR-375 | Solexa deep sequencing | Stage II-III BC | 42 | qRT-PCR | 26 | [57] |
miR-30a | miRNA microarray | IDC | 221 | NR | NR | [104] |
qRT-PCR | Heterogeneous BC | 96 | NR | NR | [108] | |
miR-342-5p | miRNA microarray | Heterogeneous BC | 101 | miRNA microarray | 1,302 | [109] |
miR-497 | qRT-PCR | Heterogeneous BC | 128 | NR | NR | [111] |
qRT-PCR | IDC | 48 | NR | NR | [110] |
miRNAs associated with negative outcome
| ||||||
---|---|---|---|---|---|---|
miRNA
|
Case cohort
|
Validation cohort
|
Reference
| |||
Detection
|
Cells of origin
|
Number of samples
|
Technique
|
Number of samples
| ||
miR-122 | Deep sequencing | Heterogeneous BC | 42 | qRT-PCR | 26 | [57] |
miR-27b-3p | qRT-PCR | TNBC | 58 | qRT-PCR | 41 | [113] |
miR-21 | qRT-PCR | IDC | 109 | NR | NR | [115] |
qRT-PCR | Heterogeneous BC | 84 | NR | NR | [102] | |
miR-210 | Deep sequencing | IDC | 118 | NR | NR | [75] |
Meta-analysis | NR | 699 | Meta-analysis | Meta-analysis | [116] | |
Meta-analysis | NR | 1,809 | Meta-analysis | Meta-analysis | [117] | |
miR-9 | miRNA microarray | ER+ BC | 16 | qRT-PCR | 52 | [120] |
miR-187 | LNA miRCURY | LN+ BC | 117 | LNA miR probe | 470 | [121] |
miR-155 | qRT-PCR | Heterogeneous BC | 88 | NR | NR | [122] |
qRT-PCR | Heterogeneous BC | 231 | NR | NR | [123] |