Table 1. List of prognostic microRNAs in breast cancer.
| Prognostic microRNA | Breast cancer type | Detection method | Prognostic value | Role | Biological sample | References |
|---|---|---|---|---|---|---|
| let-7 | BC not
classified |
qRT-PCR | potential prognostic
biomarker as altered levels of miR-let-7 are associated with metastases risk |
tumor
suppressor |
serum | [56] |
| let-7-3p | TNBC | NGS, qRT-
PCR |
independent prognostic
factor for OS, DFS |
onco-miR | FFPE | [57] |
| let-7b | luminal subtype | qRT-PCR,
LNA-ISH, TMAs |
independent prognostic
factor for OS associated with luminal tumors |
tumor
suppressor |
FFPE | [58] |
| let-7c/miR-
99a/miR-125b cluster |
estrogen-
dependent BC cell line |
Nanostring,
qRT-PCR, luciferase assay |
potential prognostic factor
for OS in the luminal A subtype |
tumor
suppressor |
cell lines | [59] |
| miR-1 | ER-positive,
stage IV BC |
PCR,
microarray, ISH, IHC |
independent worse
prognostic factor of DFS and BC-specific survival associated with stage, lymph node metastasis, distant metastasis, histological grade, ER status, PR status and Ki-67 |
onco-miR | FFPE | [60] |
| miR-7 | BC not
classified |
qRT-PCR | potential prognostic factor
for OS, DFS predictive of an adverse response to tamoxifen therapy |
onco-miR | fresh frozen
tissue, cell lines |
[61] |
| miR-9 | TNBC,
BC not classified |
qRT-PCR | prognostic factor of DFS
and DMFS, OS |
onco-miR | FFPE, fresh
frozen tissue, cell lines |
[62, 63] |
| miR-10b | BC not
classified, TNBC |
qRT-PCR | independent prognostic
factor for DFS associated with distant metastasis, occurrence in TNBC, associated with genico- obstetric history |
onco-miR | FFPE, fresh
frozen tissue, cell lines |
[17, 40, 41, 64] |
| miR-15a | TNBC | qRT-PCR | prognostic factor for OS,
DFS |
tumor
suppressor |
fresh frozen
tissue |
[65] |
| miR-16 | triple
possitive BC |
qRT-PCR,
Western blot, luciferase report assay, MTS assay |
potentially tumor
suppressive effect on cancer progression of ER positive breast cancers, impairment of cell proliferation |
tumor
suppressor |
FFPE | [45] |
| miR-19a | newly
diagnosed IBC stage III, IBC stage IV, non-IBC stage II-IV and HER2+ BC |
qRT-PCR | potential prognostic factor
for OS, DFS in patients with metastatic HER2(+) IBC. |
tumor
suppressor |
serum, cell
lines |
[66] |
| miR-19b | BC not
classified |
qRT-PCR | prognostic factor for OS
associated with distant metastasis and TNM stage |
onco-miR | fresh frozen
tissue, cell lines |
[67] |
| miR-20b-5p | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS, correlated with the presence of breast tumor interstitial fluid |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-21 | stage II/III
BC, HER2 positive, TNBC |
qRT-PCR,
microarray, luciferase report assay |
independent prognostic
factor of OS, DFS, prognostic biomarker for resistance to trastuzumab, to predict lymph node metastases occurrence in TNBC, to predict high grade in non TNBC possible, prognostic factor in daughter of patients, associated with genico- obstetric history |
onco-miR | FFPE, serum,
fresh frozen tissue, cell lines |
[16-27] |
| miR-22 | BC not
classified |
qRT-PCR,
ISH, luciferase report assay |
potential prognostic factor
for OS, DFS, associated with EMT/metastasis |
both | FFPE, cell lines | [69, 70] |
| miR-24-2*. | BC cell
lines |
qRT-PCR | associated with tumor
suppressive activity through the suppression of cellular survival |
tumor
suppressor |
cell lines, fresh
frozen mouse tissue |
[71] |
| mir-24-3p | BC not
classified (stage I-III) |
Nanostring
technology |
potential prognostic
biomarker of occult metastasis |
onco-miR | plasma | [72] |
| miR-27a | BC not
classified |
ISH, IHC | independent prognostic
factor for OS, DFS |
onco-miR | FFPE | [73] |
| miR-27b-3p | TNBC | qRT-PCR | independent prognostic
factor for OS, DMF survival |
onco-miR | FFPE | [74] |
| miR-29a | BC not
classified |
qRT-PCR,
microarray |
asocciated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-29b | lobular
and ductal subtypes |
qRT-PCR | prognostic factor for OS,
DFS |
tumor
suppressor |
fresh frozen
tissue |
[76, 77] |
| miR-30a | TNBC | NGS,
qRT-PCR, microarray, luciferase assay |
independent prognostic
factor for OS, DFS |
tumor
suppressor |
FFPE, cell lines | [57, 78] |
| miR-30a-3p | TNBC | qRT-PCR | prognostic factor for OS,
RFS |
tumor
suppressor |
FFPE | [57] |
| miR-30a-5p | TNBC | NGS | prognostic factor for OS,
RFS |
tumor
suppressor |
FFPE | [57] |
| miR-30c-5p | TNBC | qRT-PCR | prognostic factor for
RFS |
tumor
suppressor |
FFPE | [57] |
| miR-30e* | ESR1-/
ERBB2- tumors |
microarray,
ISH |
prognostic factor for DFS | tumor
suppressor |
fresh frozen
tissue |
[79] |
| miR-34a | BC not
classified TNBC |
qRT-PCR,
TMAs |
prognostic factor for OS,
associated with response and chemotherapy resistance |
both | FFPE, plasma,
cell lines |
[75, 80, 81] |
| miR-34b | TNBC | qRT-PCR | prognostic factor for OS,
DFS |
onco-miR | FFPE | [82] |
| miR-34c | TNBC | qRT-PCR | independent risk factor
for OS |
tumor
suppressor |
Plasma | [81] |
| miR-93-5p | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS, correlated with the presence of breast tumor interstitial fluid |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-95-3p | TNBC | qRT-PCR | prognostic factor for OS,
RFS in patients treated with anthracycline-based chemotherapy |
onco-miR | FFPE | [57] |
| miR-96 | BC cell
lines |
qRT-PCR | potential prognostic factor
for OS associated with EMT and regulation of growth factors involved in G1/S-phase transition |
onco-miR | cell lines | [44] |
| miR-99a | BC not
classified |
qRT-PCR | potential prognostic factor
for OS, independent risk factor for breast cancer |
tumor
suppressor |
serum | [83] |
| miR-122 | BC not
classified (stage II-III) |
qRT-PCR,
NGS |
potential prognostic
factor for disease relapse, predictor of metastasis |
onco-miR | serum | [84] |
| miR-124 | BC not
classified |
qRT-PCR | prognostic factor for
OS associated with advanced TNM stage, lymph node metastasis and poorer pathological differentiation, associated with age at diagnosis (>50 years old) |
tumor
suppressor |
FFPE, fresh
frozen tissue |
[85, 86] |
| miR-125a-5p | BC not
classified |
microarray,
qRT-PCR, luciferase assay, ISH, IHC |
potential prognostic factor
for OS, progression-free survival (PRS) |
tumor
suppressor |
serum, cell
lines |
[87] |
| miR-125b | HER2
positive BC, stage II/III |
qRT-PCR, ISH | prognostic factor for
OS, DFS, associated with aromatase inhibitor esistant breast cancers |
onco-miR | FFPE, serum,
cell lines |
[26, 88, 89] |
| miR-126-5p | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-127 | BC not
classified |
qRT-PCR | prognostic factor of OS | tumor
suppressor |
fresh frozen
tissue, cell lines |
[90] |
| miR-128-3p | TNBC | qRT-PCR | prognostic factor for RFS | tumor
suppressor |
FFPE | [57] |
| miR-129-5p | BC not
classified |
qRT-PCR,
luciferase report assay |
potential prognostic factor
for OS, DFS, associated with EMT |
tumor
suppressor |
FFPE, fresh
frozen tissue, cell lines |
[91] |
| miR-133a | BC not
classified |
qRT-PCR,
TMA, ISH, Luciferase assay |
potential prognostic factor
for DFS associated with migration and invasion |
tumor
suppressor |
FFPE, fresh
frozen tissue, cell lines |
[92] |
| miR-140 | BC not
classified |
qRT-PCR,
microarray |
asocciated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-141 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS associated with circulating tumor cells status |
onco-miR | plasma | [33, 34] |
| miR-143 | Triple
possitive BC |
qRT-PCR,
Western blot, luciferase report assay, MTS assay |
potentially tumor
suppressive effect on cancer progression of ER positive breast cancers, impairment of cell proliferation |
tumor
suppressor |
FFPE | [45] |
| miR-144 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS |
tumor
suppressor |
plasma | [34] |
| miR-145 | BC not
classified |
qRT-PCR | potential prognostic factor
for DFS, OS (3-year survival rate) |
tumor
suppressor |
fresh frozen
tissue |
[93, 94] |
| miR-146a | BRCA1-
deficient TNBC tumors |
qRT-PCR | potential prognostic factor
for OS |
tumor
suppressor |
FFPE, cell lines | [95] |
| miR-148a | TNBC | qRT-PCR,
microarray |
potential prognostic factor
for OS associated with metastasis |
tumor
suppressor |
Cell lines,
mouse models |
[96] |
| miR-155 | TNBC,
BC not classified |
qRT-PCR,
microarray, luciferase report assay |
prognostic factor of
DMFS, associated with lymph node metastasis |
both | FFPE, fresh
frozen tissue, cell lines |
[62, 97] |
| miR-182 | BC not
classified, TNBC |
qRT-PCR | potential prognostic factor
to predict lymph node metastases occurrence in TNBC, associated with genico-obstetric history, related with hormonal receptors |
onco-miR | FFPE, serum | [17, 98] |
| miR-183/182/96
cluster |
BC not
classified |
qRT-PCR, ISH | potential prognostic factor
for OS, DFS |
onco-miR | breast tissues
not classified, cell lines |
[99] |
| miR-187 | BC not
classified |
TMA, ISH | independent prognostic
factor FOR breast cancer– specific survival (BCSS) |
onco-miR | FFPE, cell lines | [100] |
| miR-193b | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS |
onco-miR | plasma | [34] |
| miR-195-5p | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-199a-5p | TNBC | NGS | prognostic factor for OS | tumor
suppressor |
FFPE | [57] |
| miR-199b-5p | BC not
classified (-II stage) |
qRT-PCR,
assays in vitro |
potential prognostic factor
for OS associated with TNM stage and lymph node metastasis |
tumor
suppressor |
fresh frozen
tissue and cell lines |
[101] |
| miR-200a | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS, associated with circulating tumor cells status, potential to detect the onset of metastasis |
onco-miR | plasma | [33, 34] |
| miR-200b | BC not
classified |
qRT-PCR,
microRNA arrays, ISH, TMA, luciferase report assay |
potential prognostic factor
for OS (independent), PFS associated with advanced clinical stage, metastasis, cell proliferation, apoptosis, cell cycle distribution and circulating tumor cells status, potential to detect the onset of metastasis |
both | FFPE, plasma,
cell lines |
[33, 34, 46, 47] |
| miR-200c | BC not
classified |
qRT-PCR,
microRNA arrays |
prognostic factor of OS,
DFS, potential to detect the onset of metastasis, associated with circulating tumor cells status |
onco-miR | fresh frozen
tissue, plasma |
[33, 34, 102] |
| miR-200c/141
cluster |
BC not
classified, TNBC |
qRT-PCR,
CAT reporter assay, siRNA transfection, Western blot |
poor prognostic factor
in TNBC, promoting metastasis |
onco-miR | FFPE, cell
lines, xenograft animal model |
[103] |
| miR-203 | BC not
classified, ER positive BC |
microRNA
arrays, qRT- PCR, Western blot, luciferase report assay, MTS assay |
potential prognostic factor
for OS, PFS associated with EMT and circulating tumor cells status |
both | FFPE, plasma,
cell lines |
[33, 34, 44, 45] |
| miR-203-5p | TNBC | NGS | prognostic factor for OS | onco-miR | FFPE | [57] |
| miR-203a | ductal
in situ, invasive ductal and lobular carcinoma |
qRT-PCR | potential prognostic
marker associated with increased stage in invasive lobular carcinomas |
tumor
suppressor |
FFPE | [104] |
| miR-204 | BC not
classified |
qRT-PCR | potential prognostic factor
for OS, DFS, correlated with chemotherapeutic resistance |
tumor
suppressor |
FFPE | [105] |
| miR-205 | BC not
classified |
qRT-PCR,
LNA-ISH, TMAs, IHC |
potential prognostic
factor for OS associated with tumours of ductal morphology, for OS and DFS in early breast cancer |
tumor
suppressor |
FFPE | [21, 58] |
| miR-206 | BC not
classified |
qRT-PCR,
luciferase report assay |
potential prognostic factor
for OS |
both | fresh frozen
tissue, cell lines |
[94, 106, 107, |
| miR-210 | early first
primary BC, TNBC |
qRT-PCR,
microarray |
independent prognostic
factor for OS, DFS, associated with poor clinical outcome in ER- positive, tamoxifen-treated BC patients, involved in cell proliferation, migration and invasion, Potential to detect the onset of metastasis prior to clinical diagnosis, associated with circulating tumor cells status |
onco-miR | FFPE, fresh
frozen tissue, plasma, cell lines (Breast cancer and tumor-educated macrophages) |
[33-39] |
| miR-210-3p | BC cell
lines |
qRT-PCR | potential prognostic factor
for OS associated with EMT and regulation of growth factors involved in G1- to S-phase transition |
onco-miR | cell lines | [44] |
| miR-215 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS, Potential to detect the onset of metastasis prior to clinical diagnosis |
tumor
suppressor |
plasma | [34] |
| miR-218 | BC not
classified |
qRT-PCR | prognostic factor for OS
associated with lymph node metastases, higher grades, |
tumor
suppressor |
fresh frozen
tissue |
[108] |
| miR-221 | BC not
classified |
qRT-PCR | prognostic factor for DFS,
OS, RFS |
onco-miR | FFPE, fresh
frozen tissue, cell lines |
[41, 63, 109] |
| miR-221-3p | TNBC | qRT-PCR | prognostic factor for DFS | tumour
suppressor |
FFPE, cell lines | [110] |
| miR-222 | BC not
classified |
qRT-PCR,
TMA |
potential prognostic
factor related to lymph node metastasis, down- regulation of the estrogen receptor, EMT, tumor progression, poor response and chemotherapy resistance |
onco-miR | FFPE, fresh
frozen tissue, cell lines |
[75, 109] |
| miR-222-3p | BC not
classified |
qRT-PCR,
microarray |
independent prognostic
factor for DFS postoperatively |
onco-miR | serum | [111] |
| miR-301a | BC not
classified, TNBC |
qRT-PCR,
microarray, ISH |
prognostic factor for DFS,
OS |
onco-miR | FFPE | [112, 113] |
| miR-320a | BC not
classified |
chromogenic
ISH |
potential prognostic factor
for OS for invasive breast cancer |
tumor
suppressor |
FFPE | [114] |
| miR-324-5p | TNBC | NGS | prognostic factor for OS | onco-miR | FFPE | [57] |
| miR-329 | BC not
classified |
qRT-PCR | independent prognostic
factor for OS |
tumor-
suppressor |
serum, fresh
frozen tissue, cell lines |
[115] |
| miR-330-3p | BC not
classified |
qRT-PCR | potential prognostic factor
for OS |
onco-miR | fresh frozen
tissue |
[116] |
| miR-339-5p | BC not
classified |
qRT-PCR,
TMA, ISH |
independent prognostic
factor for OS, DFS |
tumor
suppressor |
FFPE, cell lines | [117] |
| miR-361-5p | BC not
classified, TNBC |
TMAs, ISH | prognostic factor for DFS | tumor
suppressor |
FFPE | [118] |
| miR-365 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS |
miR-365,
onco-miR |
plasma | [34] |
| miR-370 | BC not
classified |
qRT-PCR,
TMA |
potential prognostic factor
for DFS |
onco-miR | FFPE | [119] |
| miR-374a | BC not
classified, IDC stage II |
qRT-PCR,
TMAs, Luciferase assay, MTT assays, IHC |
potential prognostic factor
for DFS, contributes to tumorigenicity and progression |
onco-miR | FFPE, fresh
frozen tissue, cell lines, xenograft mouse models |
[120, 121] |
| miR-375 | BC not
classified, stage II-III locally advanced and IBC patients |
qRT-PCR,
microRNA arrays, NGS |
potential prognostic factor
for OS, PFS associated with circulating tumor cells status, related to hormonal receptors |
both | serum, plasma | [33, 34, 84, 98] |
| miR-409-3p | BC not
classified |
qRT-PCR | independent prognostic
factor for OS associated with advanced TNM stage, lymph node metastasis, and poorer pathological differentiation |
tumor
suppressor |
fresh frozen
tissue |
[112] |
| miR-423 | BC not
classified |
qRT-PCR,
microarray |
asocciated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-429 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS |
miR-429
onco-miR |
plasma | [34] |
| miR-451 | BC cell
lines |
qRT-PCR | potential factor associated
with cell survival and endocrine resistance |
tumor
suppressor |
cell lines | [123] |
| miR-454 | BC not
classified (stage I-III) |
TMA, ISH | potential prognostic
factor for OS (especially in TNBC) and DFS, associated with response to anthracycline |
onco-miR | FFPE | [124] |
| miR-454-3p | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-486-5p | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, Potential to detect the onset of metastasis prior to clinical diagnosis |
tumor
suppressor |
plasma | [34] |
| miR-493 | TNBC | TMAs, ISH | prognostic factor for DFS | tumour
suppressor |
FFPE | [125] |
| miR-494 | node-
negative BC |
ISH | 8.5-fold risk of breast
cancer death (association trend-not clinical significance) |
tumour
suppressor |
fresh frozen
tissue |
[126] |
| miR-497 | BC not
classified, TNBC |
qRT-PCR,
luciferase assay |
potential prognostic factor
for OS |
tumor
suppressor |
fresh frozen
tissue, cell lines, orthotopic mouse models |
[127, 128] |
| miR-548c-5p | TNBC | qRT-PCR, ISH | independent prognostic
factor for OS, DFS |
onco-miR | FFPE | [39] |
| miR-574 | BC not
classified |
qRT-PCR,
microarray |
asocciated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-574-3p | BC not
classified |
qRT-PCR,
NGS |
potential prognostic factor
for OS, DFS |
tumor
suppressor |
FFPE | [129] |
| miR-588 | BC not
classified |
qRT-PCR | prognostic factor of OS | tumour
suppressor |
fresh frozen
tissue, cell lines |
[130] |
| miR-590-3p | BC cell
lines |
qRT-PCR,
luciferase report assay |
associated with breast
cancer cells viability, growth and apoptosis |
tumor
suppressor |
cell lines | [131] |
| miR-597 | BC not
classified |
qRT-PCR | prognostic factor of OS | tumor
suppressor |
fresh tissue | [132] |
| miR-601 | BC not
classified |
qRT-PCR | prognostic factor for
DFS associated with cell proliferation and metastasis |
tumor
suppressor |
FFPE, cell lines | [133] |
| miR-638 | BC not
classified, BRCA1- deficient TNBC tumors |
qRT-PCR | independent prognostic
factor for OS associated with lymph node metastasis and TNM stage |
tumor
suppressor |
FFPE, fresh
frozen, cell lines |
[95, 134] |
| miR-644a | BC cell
lines |
qRT-PCR,
luciferase report assay |
associated with tumor
progression and distant metastasis-free survival |
tumor
suppressor |
cell lines | [135] |
| miR-660-5p | BC not
classified |
qRT-PCR,
NGS |
potential prognostic factor
for OS, DFS |
onco-miR | FFPE | [129] |
| miR-711 | BC not
classified |
qRT-PCR | independent prognostic
factor for OS, DFS, associated with breast cancer cells’ proliferation, colony formation, invasion |
onco-miR | FFPE, cell lines | [136] |
| miR-744 | BC not
classified |
qRT-PCR,
microarray |
associated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-801 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS associated with circulating tumor cells status |
onco-miR | plasma | [33, 34] |
| miR-874 | BC not
classified |
qRT-PCR | prognostic factor for OS | tumour
suppressor |
fresh frozen
tissue, cell lines |
[137] |
| miR-940 | IDC, TNBC | qRT-PCR | prognostic factor for OS | tumor suppressor | serum | [138] |
| miR-1179 | BC not
classified |
RT-PCR | independent prognostic
factor for OS |
tumor
suppressor |
breast tissue
not classified, cell lines |
[139] |
| miR-1247-5p | BC not
classified |
qRT-PCR | independent prognostic
indicator for DFS, OS |
tumor
suppressor |
FFPE, fresh
frozen tissue, cell lines |
[140, 141] |
| miR-1260 | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS |
onco-miR | plasma | [34] |
| miR-1274a | BC not
classified |
microRNA
arrays, qRT- PCR |
potential prognostic factor
for OS, PFS |
onco-miR | plasma | [34] |
| miR-1274b | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-1825 | BC not
classified |
microRNA
arrays |
potential prognostic factor
for DFS |
onco-miR | FFPE,
interstitial breast tumor fluids, serum |
[68] |
| miR-3178 | BC not
classified |
qRT-PCR,
microarray |
associated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
| miR-4653-3p | HR+ BC
(stage I~III) |
qRT-PCR | potential prognostic
biomarker for DFS for patients treated with adjuvant tamoxifen |
tumor
suppressor |
FFPE | [142] |
| miR-6780b | BC not
classified |
qRT-PCR,
microarray |
associated with
poor response and chemotherapy resistance |
onco-miR | FFPE, cell lines | [75] |
Abbreviations: quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR), In situ hybridization (ISH), locked nucleic acid probe in situ hybridization (LNA-ISH), Immunohistochemistry (IHC), epithelial-mesenchymal transition (EMT), formalin-fixed paraffin embedded (FFPE), Next Generation Sequencing (NGS), overall survival (OS), relapse free survival (RFS), disease free survival (DFS), progress free survival (PFS), breast cancer (BC), triple negative breast cancer (TNBC), Inflammatory breast cancer (IBC), Invasive Ductal Carcinoma (IDC), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor type 2 (HER2).