Review Article

Regulation of Breast Cancer and Bone Metastasis by MicroRNAs

Table 1

Targets of oncogenic miRNAs and their role in cancer cells.

miRNAs Target geneTechniquesShort descriptionReferences

miR-21TPM1WB, LAmiR-21 downregulates TPM1 in breast cancer and leads to anchorage-independent growth.[25]
E2F1WB, RT-PCRmiR-21 regulates E2F1 by TGF-β signaling pathway.[55]
TGFBR2WB, RT-PCRmiR-21 regulates TGFBR2 by TGF-β signaling pathway.[55]
TIMP3WB, RT-PCRTIMP3 is a MMP inhibitor, miR-21 suppresses TIMP3 by promoting invasiveness of cancer cells.[56]
SERPINB5WB, LADownregulation of PDCD4 and maspin (SERPINB5) by miR-21 causes tumorogenesis.[57]
PDCD4WB, RT-PCR, LAmiR-21 decreases PDCD4 protein amounts and increases invasion.[58]
FAS, CDK6, PDCD4, CDKN1A, FAM3C, HIPK3, PRRG4, ACTA2, BTG2, BMPR2, SESN1, IL6R, SOCS5, GLCCI1, APAF1,
SLC16A10, SGK3, RP2, CFL2
RT-PCR, MInhibition of miR-21 in MCF-7 breast cancer cells shows reduced expression of p53 tumor suppressor protein. FAS, CDK6, CDKN1A, FAM3C, HIPK3, PRRG4, ACTA2, BTG2, BMPR2, SESN1, IL6R and tumor suppressor protein Programmed Cell Death 4 (PDCD4) are also downregulated by miR-21. [30]
FAS, TIMP3WB, LADownregulation of miR-21 increases Fas ligand and TIMP3 expression; thereby it is involved in the upregulation of apoptosis.[59]
CDC25AWB, RT-PCR, LAmiR-21 suppresses Cdc25A expression, a cell cycle regulator.[60]
RECKRT-PCRmiR-21 suppresses RECK and inhibitors of MMPs and thus promotes invasiveness of cancer cells.[56]
MTAPLAApoptotic function of MTAP is suppressed by miR-21.[61]
RECKWB, RT-PCR, LARECK regulating the membrane-anchored protease is down regulated by miR-21.[62]
PDCD4WB, LAmiR-21 positively regulates PDCD4 through interaction with ovarian steroids and TGF-β signaling pathway.[55]
BTG2EGFP, WB, Fluorescence Intensity Expression of miR-21 leads to lower level of BTG2 which is a cell cycle regulator and tumor suppressor. It causes loss of control on G1 to S phase transition.[63]
PTENLAmiR-21 regulates MMP-2 expression in cardiac fibroblasts of the infarct zone via PTEN pathway.[64]
BTG2WB, RT-PCR, LAmiR-21 directly inhibits BTG2 which is a cell cycle inhibitor leading to uncontrolled DNA synthesis by activation of forkhead box M1.[65]
PELI1RT-PCR, LAmiR-21 overexpression inhibits Peli1 via kappaB signalling.[66]
PDCD4WBDeregulation of miR-21 by vinyl carbamate induces mouse lung tumorigenesis by down regulating PDCD4.[67]
BIG-H3 LAmiR-21 targets big-h3. It could be induced by TGF-β and it regulates TGF-β signalling positively and negatively.[68]
BIMWB, LABim, a apoptotic activator, is collectively targeted by miR-21, miR-24, and miR-221 and its action is suppressed.[69]
HER2WB, RT-PCRmiR-21 upregulates human epidermal growth factor receptor 2 and acts as oncogene.[34]
MSH2, SMAD7WB, RT-PCR, LAmiR-21 downregulates MSH2 and SMAD7 in TGF-β pathway and causes breast cancer progression.[33]

miR-10bHOXD10WB, LAOverexpression of miR-10b induces robust invasion and metastasis by down regulating translation of homeobox D10.[37]
KLF4WB, RT-PCR, LA miR-10b reduces endogenous KLF4 protein, a tumor suppressor.[70]
SFRS1 WB, RT-PCR, LAmiR-10b suppresses SFRS1 (SR-family splicing factor) and causes migration, invasion, and in vivo metastasis of neuroblastoma cells.[71]
SFRS10LAmiR-10b suppresses SFRS10 and causes migration, invasion, and in vivo metastasis of neuroblastoma cells.[71]

miR-125a-5pERBB2WB, RT-PCR, LAExpression of either miR-125a or miR-125b results in suppression of ERBB2 and ERBB3 (oncogene family) and exhibits reduced migration and invasion capacities.[72]
TP53WB, RT-PCR, LAmiR-125b inhibits p53 gene translationally and transcriptionally and the isomer of miRNA-125 (miRNA-125a) translationally arrests mRNA of the p53, a tumor suppressor gene.[44]
HuRWB, RT-PCR, LAHuR is a stress induced RNA binding protein having over expression in different cancers. Expression of miR-125a significantly reduces HuR.[73]
ARID3BWBARID3B is overexpressed in human ovarian cancer. Overexpression of miR-125a induces conversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial morphology and suppresses cancer by negatively regulating EMT.[74]

miR-125bBAK1WB, RT-PCR, LA, MOverexpression of miR-125b stimulates androgen-independent growth of prostate cancer by down regulating Bak1 (proapoptotic regulator).[75]
CDK6, CDC25AWBmiR-125b overexpression decreases CDK6 and CDC25A expression. It regulates proliferation of U251 glioma stem cells through cell cycle regulated proteins CDK6 and CDC25A.[76]
SMOWB, RT-PCR, LADownregulation of miR-125b allows high levels of Hedgehog-dependent gene expression leading to tumor cell proliferation by allowing Hedgehog signalling.[77]
ST18WB, Branched, LA, DNA Probe AssayST18 is downregulated in DS-AMKL patients having high expression of miR-125b; thus miR-125b-2 acts as a positive regulator of megakaryopoiesis.[78]
DICER1WB, LA, Branched DNA Probe AssayDICER1 is down regulated in DS-AMKL patients having high expression of miR-125b, thus miR-125b-2 acts as a positive regulator of megakaryopoiesis. [78]
TP53INP1LAmiR-125b directly represses TP53INP1, an apoptosis regulator in p53 pathway. [79]
BMFWB, RT-PCR, LAoverexpression of miR-125b reduces expression of cell apoptosis related protein Bcl-2 modifying factor (Bmf), by targeting BMF.[80]
BMPR1BLAmiR-125b targets BMPR1B and causes risk in breast cancer pathogenesis.[81]
HuRWBHuR is a stress-induced RNA binding protein having over expression in different cancers. miR-125a targets HuR.[82]
κB-Ras2LAmiR-125b downregulates kappaB-Ras2 gene expression.[83]
E2F3WB, RT-PCR, LAE2F3, an inducer of bladder cancer, is suppressed by miR-125b at protein level through regulation of G1/S transition through the E2F3-Cyclin A2 signaling pathway.[84]
PUMALAmiR-125b directly represses Puma, an apoptosis regulator in p53 pathway.[79]
BAK1, CDC25C,
PPP1CA, PPP2CA, PRKRA, TDG,TP53, ZAC1
LAmiR-125b directly represses apoptosis regulators such as BAK1, CDC25C, PPP1CA, PRKRA and TP53A, ZAC1, in p53 pathway. [79]
PPP2CART-PCR, LAmiR-125b directly inhibits apoptosis by down regulating PPP2CA expression.[85]
TDGqRT-PCRmiR-125b directly suppresses the expression of TDG in p53 pathway.[86]

miR-155CYR61WB, RT-PCR, LAoverexpression of miR-155 contributes to preeclampsia development by targeting and downregulating angiogenic regulating factor CYR61. [87]
FOXO3WB, RT-PCR, LAInverse correlation between miR-155 and FOXO3a prevails in breast cancer cell lines and tumors.[47]
SOCS1Immunofluorescence, RT-PCR, LAOverexpression of miR-155 in breast cancer cells leads to constitutive activation of signal transducer and activator of transcription 3 (STAT3) through the Janus-activated kinase (JAK) pathway.[88]
CCND1LAmiR-155 reduces endogenous expression of CCND1 by suppressing Luc-CCND1.[89]
IKBKEWB, RT-PCR, LAmiR-155 expression is increased in gastric epithelial cell lines and gastric mucosal tissues.
miR-155 negatively regulates IkappaB kinase epsilon, Sma- and Mad-related protein 2 (SMAD2), Fas-associated death domain protein, interleukin-8, and growth-related oncogene-alpha.
[90]
FADDWB, RT-PCRmiR-155 expression is increased in gastric epithelial cell lines and gastric mucosal tissues.
miR-155 negatively regulates IkappaB kinase epsilon, Sma- and Mad-related protein 2 (SMAD2), Fas-associated death domain protein, interleukin-8, and growth-related oncogene-alpha.
[90]
JARID2WB, RT-PCR, LAoverexpression of miR-155 decreases levels of endogenous JARID2, cell cycle regulator mRNA and causes tumor.[91]
CEBPBWB, RT-PCR, LAEBPβ translation is suppressed by miR-155 through C/EBPβ in tumor-activated monocytes and reduces tumor progression.[92]
SHIPWB, RT-PCR, LAmiR-155 decreases SHIP1 expression as a result of autocrine stimulation by proinflammatory cytokine tumor necrosis factor alpha (TNF-α).[93]
TAM WB, RT-PCRmiR-155 downregulates TAM and causes spontaneous breast cancer development.[94]
VHLWB, RT-PCRmiR155 downregulates VHL, tumor suppressor via promoting HIF transcription factors and angiogenesis.[95]
p53WB, RT-PCR, LAmiR155 downregulates p53 and promotes cell proliferation.[52]
VHLWB, RT-PCR, LAmiR155 downregulates VHL and promotes lymph node metastasis and poor prognosis as well as triple-negative tumor in breast cancer.[54]
CDC73WB, RT-PCR, LAmiR155 negatively regulates CDC73 which inturn positively regulates β-catenin, cyclin D1, and c-MYC and increases cell viability.[53]
ZNF652WB, RT-PCRmiR155 downregulates ZNF652 causing expression of TGFB1, TGFB2, TGFBR2, EGFR, SMAD2, and VIM resulting in increased cell invasion and metastasis.[96]
MMP2, MMP9, VEGF WB, RT-PCRmiR155 causes up regulation of MMP2, MMP9, and VEGF resulting in increased tumor size.[97]
HK2WB, RT-PCR, LAmiR155 up regulates hk2 by activating signal transducer and activator of transcription 3 (STAT3 ) and targeting C/EBPβ.[48]

WB: Western blot; RT-PCR: real time-PCR; LA: luciferase Assay; M: microarray.