Sage Journals: Discover world-class research

Abstract

The microRNA family, miR-30, plays diverse roles in regulating key aspects of neoplastic transformation, metastasis, and clinical outcomes in different types of tumors. Accumulating evidence proves that miR-30 family is pivotal in the breast cancer development by controlling critical signaling pathways and relevant oncogenes. Here, we review the roles of miR-30 family members in the tumorigenesis, metastasis, and drug resistance of breast cancer, and their application to predict the prognosis of breast cancer patients. We think miR-30 family members would be promising biomarkers for breast cancer and may bring a novel insight in molecular targeted therapy of breast cancer.

Keywords

MicroRNA miR-30 family biomarker breast cancer

Introduction

The past decade has shown remarkable significance in microRNA (miRNA) functions ranging from physiological mechanism to pathological process. These endogenous noncoding small RNAs, which consist of 20 to 22 nucleotides, negatively regulate posttranscriptional expressions of target genes by binding to the 3′-untranslated region (UTR) of target messenger RNAs (mRNAs), thus resulting in corresponding mRNA degradation or translational inhibition.¹ In recent years, accumulating evidence has demonstrated that some miRNAs are aberrantly expressed in various cancer types, such as lung cancer,² multiple myeloma,³ breast cancer,^4,5 colorectal cancer,⁶ glioma,⁷ and hepatocellular carcinoma (HCC).⁸ Indeed, miRNAs, either as tumor suppressor or promoter, are shown to take part in many cancer-related bioprocesses, including tumorigenesis, cell proliferation, differentiation, apoptosis, angiogenesis, invasion, and metastasis.^9,10

Breast cancer, as the leading cause of cancer-induced mortality among women around the world,¹¹ has been drawn much attention in the relations between miRNAs and its pathophysiology.^12,13 Notably, miRNAs and their targets perform an orchestrated network in breast cancer, and the miRNA expression analysis has identified several promising markers for diagnosis, prognosis, and treatment of breast cancer.^14,15 In this regard, accumulating evidence demonstrates that miR-30 family members, significantly downregulated in breast cancer, and act as tumor suppressor during breast growth, metastasis, and drug resistance.^16,17

In this review, we aim at reviewing the most common roles of miR-30 family members in the development of breast cancer, focusing on recent advancements on miR-30 family members as novel cancer-related biomarkers. Altogether, these studies underscore the potential applications of miR-30 family members for the prognosis and treatment of breast cancer.

Overview of miR-30 family in tumors

Genomic location of miR-30 family members

The miR-30 family, which contains five members and six distinct mature miRNAs (miR-30a, -30b, -30c-1, -30c-2, -30d, -30e),¹⁸ is encoded by six genes located on human chromosomes 1, 6, and 8 (Figure 1).These miRNAs share the same seed sequence located near the 5′end, but have different compensatory sequences located near the 3′end. The differences in compensatory sequences allow miR-30 family members to target different genes and pathways,¹⁹ and sometimes lead to totally opposite behaviors. Consistently, a variety of physiological and pathological conditions have been correlated to a differential expression of miR-30 family members through altering targeted gene expressions. Accumulating studies demonstrate that miR-30 family members, either as tumor suppressor miRNAs or onco-miRNAs, were described as a function center of the miRNA signal network involved in oncogenesis and invasion in different types of tumors²⁰ (Table 1), especially breast cancer.

Figure 1.

miR-30 family members and their genomic locations. (a) Genomic location of miR-30 family members. (b) Mature sequences of miR-30 family members that arise from the 5′arm of the precursors. The seed sequences highlighted in red and green represent conserved nucleotides. (c) Mature sequences of miR-30 family members that arise from the 3′arm of the precursors.

Table 1.

miR-30 family members in different types of tumors.

Tumors	miRNAs	Targets	Tumor suppressor- (S) OR onco-miRNAs (O)	Functions	References
Acute myeloid leukemia (AML)	miR-30c	NOTCH1	S	Necessary for C/EBP alpha to block Notch1 and to induce myeloid differentiation.	Katzerke et al.²¹
Bladder cancer	miR-30b	prognostic marker	O	Overexpressed in bladder cancer tissues.	Mahdavinezhad et al.²²
Breast cancer	miR-30 family	FOXD1, AVEN	S	Inhibition of tumor growth.	Ouzounova²³
Breast cancer	miR-30a	VIM	S	Reduced tumor migration and invasion.	Cheng et al.²⁴
Colorectal cancer	miR-30a	IRS2	S	Suppressed cancer cell growth.	Zhang et al.²⁵
Chronic myeloid leukemia (CML)	miR-30e	ABL	S	Induced apoptosis and sensitized tumor to imatinib treatment.	Hershkovitz-Rokah et al.²⁶
Cervical carcinoma	miR-30 family	B-Myb	S	Induced Rb-driven cellular senescence.	Martinez et al.²⁷
Endometrial cancer	miR-30c	MTA1	S	Inhibition of metastasis and invasion.	Kong et al.²⁸ and Zhou et al.²⁹
Glioma	miR-30	Jak/STAT3 signaling pathway	O	Increased the tumorigenecity	Che et al.³⁰
Glioma	miR-30c	GFAP, STAT3	O	Regulated self-renewal and neural differentiation.	Chao et al.³¹
Gastric cancer	miR-30	Beclin-1	S	Induced autophagic cell death and cell proliferation arrest.	Yang and Pan³²
Hepatocellular carcinoma	miR-30a	SNAI1	S	Reduced invasion and metastasis.	Liu et al.³³
	miR-30c	IER2	S	Inhibition of migration and invasion.	Wu et al.³⁴
	miR-30a	vimentin	S	Inhibition of EMT.	Liu et al.³⁵
Laryngeal carcinoma	miR-30b	p53	S	Enhanced p53 gene therapy-induced apoptosis.	Li et al.³⁶
Multiple myeloma	miR-30-5p	BCL9	S	Reduced tumor burden and metastatic potential.	Zhao et al.³
Medulloblastoma	miR-30b miR-30d	prognostic marker	O	As putative oncogenic targets of a novel recurrent medulloblastoma amplicon.	Lu et al.³⁷
Malignant peripheral nerve sheath tumor	miR-30a miR-30d	KPNB1 pathway	O	Blocked tumor cell growth and survival.	Zhang et al.^38,39
Non small cell Lung cancer	miR-30b	Cthrc1	S	Inhibition of invasion and migration.	Chen et al.⁴⁰
Non small cell Lung cancer	miR-30c	MTA1	S	Inhibition of invasion.	Chen et al.⁴¹
Nasopharyngeal carcinoma	miR-30a	E-cadherin	O	Promoted invasiveness and metastasis through EMT.	Wang et al.⁴²
Ovarian cancer	miR-30c-2*	BCL9	S	Suppressed growth factor-induced cellular proliferation.	Jia et al.⁴³
Oral squamous cell cancers	miR-30b	prognostic marker	O	Frequently amplified in oral squamous cell cancers (OSCCs).	Shao et al.⁴⁴
Prostate cancer	miR-30c	cyclin D1/D2	S	Contributed to anti-cancer properties of sulfuretin.	Poudel et al.⁴⁵
Renal cell carcinoma	miR-30c	E-cadherin	S	Inhibition of EMT.	Huang et al.⁴⁶
Thyroid carcinoma	miR-30d	EZH2	S	Inhibition of cancer progression.	Esposito et al.⁴⁷

BCL9: B-cell lymphoma 9; MTA1: metastasis-associated protein 1; FOXD1: forkhead box D1; AVEN: apoptosis and caspase activation inhibitor; VIM: vimentin; EMT: epithelial–mesenchymal transition; Cthrc1: collagen triple helix repeat containing 1; KPNB1: karyopherin subunit beta 1; SNAI1: snail family zinc finger 1; IER2: immediate early response protein 2; STAT3: signal transducer and activator of transcription; GFAP: glial fibrillary acidic protein; IRS2: insulin receptor substrate 2; NOTCH1: Notch 1; EZH2: enhancer of zeste 2.

miR-30 family members as tumor suppressor miRNAs

Most of the relevant studies show that miR-30 family members act as tumor suppressors, which were frequently discovered to be downregulated in multiple types of tumors, such as lung cancer,⁴⁸ HCC,³³ and gastric cancer.⁴⁹ Moreover, miR-30d and miR-30a were identified as anti-metastasis factors in different tumors.^50,51 Several studies found that some of miR-30 family members reversed chemoresistance and/or promoted cancer cells apoptosis.^26,52 These findings were later confirmed in prostate cancer,⁵³ breast tumor,²³ clear cell renal cell carcinoma¹⁵ and acute myeloid leukemia.⁵⁴ miR-30 family members were also shown to suppress oncogenic abilities by affecting other signal pathways, such as interference with the epithelial–mesenchymal transition (EMT),⁵³ induction of Rb-driven cellular senescence via binding the 3′-UTR of B-Myb,²⁷ inhibition of self-renewal capacity and promotion of apoptosis through silencing Ubc9 (ubiquitin-conjugating enzyme 9) and ITGB3 (integrinβ3).⁵⁵

miR-30 family members as onco-miRNAs

However, since one miRNA may have many different target genes in different cells,⁵⁶ several miR-30 family members were reported to be tumor-promoting and cell-specific. The overexpression of miR-30a, which acts as an oncogene, could upregulate BCL2A1, IER3, and cyclin D2 by inhibiting FOXL2 in granulosa cell tumors.⁵⁷ Moreover, miR-30a was notably upregulated in ovarian serous adenocarcinoma, and its knockdown significantly suppressed the proliferation and migration of ovarian cancer cells.⁵⁸ Like miR-30a, both miR-30d and -30b also play significant roles in promoting cellular invasion and immunosuppression in melanoma.⁵⁹

Interestingly, both miR-30a and -30d were proved to block tumor growth and invasion in non-small cell lung cancer.^60,61 These differential behaviors may be due to the different targeting ends or different types of tumors.^42,62 Indeed, these behaviors were not unique and also found in the well-studied miR-200 family.⁶³ Therefore, summarizing the roles of miR-30 family members in a certain specific tumor—breast cancer (Table 2)—is necessary for both scientific research and clinical treatment.

Table 2.

The role of miR-30 family members in breast cancer.

miRNAs	Target	Function	Cell lines/tumor subtype	References
miR-30a	metadherin	Suppression of tumor growth.	MCF-7, MDA-MB-231, T47D	Zhang et al.¹⁶
miR-30a	Eya2	Suppression of proliferation and migration	ZR75-1, MCF-7	Fu et al.⁶⁴
miR-30a	vimentin	Inhibition of migration and invasion. Prognostic marker for cancer metastasis.	Hs578T, MDA-MB-231	Cheng et al.²⁴
miR-30b	CCNE2	Trastuzumab therapy prognostic factor.	SKBR3, BT474 (HER2-positive)	Ichikawa et al.⁶⁵
miR-30c	KRAS, MAPK	Suppression of tumor growth.	MDAMB-436	Tanic et al.⁶⁶
miR-30c	TWF1, VIM	Inhibition of invasion.	BT-20, MDA-MB-231	Bockhorn et al.⁶⁷
miR-30c	YWHAZ	Sensitized MCF7/ADR cells to doxorubicin.	MCF-7, MDA-MB-231	Fang et al.¹⁷
miR-30c	TWF1	Inhibition of chemoresistance.	T47D, MCF-7, MDA-MB-231, BT-20, HCC-70, HCC-38	Bockhorn et al.⁶⁸
miR-30c		Independent predictor of endocrine therapy in advanced estrogen receptor positive breast tumor.	ER-α positive subtype	Rodriguez-Gonzalez et al.⁶⁹
miR-30e*		Independent subtype-specific prognostic marker in breast cancer.	ESR1+/ERBB2- subtype	D’Aiuto et al.⁷⁰
miR-30 family	Ubc9, ITGB3	Reduced self-renewal and metastasis in breast tumor-initiating cells.	SKBR3,	Yu et al.⁵⁵
miR-30 family	AVEN, FOXD1	Regulated nonattachment growth.	MCF-7, 4T1(mouse)	Ouzounova²³

Eya2: eyes absent 2; CCNE2: cyclin E2; KRAS: Kirsten rat sarcoma viral oncogene homolog; MAPK: mitogen-activated protein kinases; TWF1: Twinfilin 1; VIM: Vimentin; YWHAZ: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta; Ubc9: ubiquitin-conjugating enzyme 9; ITGB3: integrinβ3; AVEN: apoptosis and caspase activation inhibitor; FOXD1: forkhead box D1.

Functions of miR-30 family members in tumorigenesis

Tumorigenesis is always related to many factors, and dysregulation of miRNA expression has been proved important in the regulation of breast cancer development.^71,72 The miR-30 family members that mainly function as tumor suppressors could cause tumor inhibition,¹⁶ apoptosis,⁵⁵ and cell cycle arrest⁶⁴ through negative regulation of oncogenes and oncogenic pathways (Figure 2).

Figure 2.

miR-30 family members in tumorigenesis. miR-30 family members act as tumor suppressors by targeting oncogenes such as Ubc9, ITGB3, AVEN, MTDH. miR-30a overexpression induces cell apoptosis and G1 cell cycle arrest through AVEN and Eya protein, respectively. Moreover, miR-30c promotes tumor growth through the activation of KRAS/MAPK signal pathway.

Mediation of MTDH (metadherin)

MTDH, also known as astrocyte elevated gene-1 (AEG-1) or 3D3/LYRIC, participates in multiple pathological steps and is highly correlated with cancer progression, including carcinogenesis, metastasis, and chemoresistance.⁷³ Downregulation of MTDH mediated by miR-30a and other miR-30 family members could suppress proliferation and tumorigenesis in breast cancer cells.¹⁶ Furthermore, clinicopathological analysis revealed that downregulation of miR-30a expression level was significantly associated with lymph node metastasis (LNM). A more recent study also revealed that miR-30d posttranscriptionally suppressed expression of the oncoprotein MTDH and reduced cell proliferation and induces apoptosis in renal cell carcinoma.⁷⁴ Therefore, in light of their involvement in tumor progression, a miR-30 family-MTDH-based therapeutic strategy could prove to be promising.

Suppression of Eya2 (eyes absent 2)

Recently, the Eya family, which modulates eye development, embryonic development, and organ differentiation,^75,76 was found involved in angiogenesis,⁷⁷ tumor initiation,⁷⁸ and metastasis in several types of cancers, including lung, breast, and ovarian cancers.^79–81

It has been reported that Eya protein blocked protein tyrosine phosphatase activity, which promotes the growth, transformation, and metastasis of breast tumor.⁸¹ Consistent with these findings, Eya2, a direct target of miR-30a, was found to upregulate in breast cancer tissues and thus facilitate tumor proliferation and migration in breast cancer progression.⁶⁴ Furthermore, the miR-30a/Eya2 axis could administer G1/S cell cycle progression, accompanied by the regulation of expression of cell cycle-related proteins, including cyclin A/D1/E and c-Myc.

Blocking of KRAS/MAPK pathway

Kirsten rat sarcoma viral oncogene homolog (KRAS)/mitogen-activated protein kinases (MAPK) pathways, which enhance tumorigenesis and tumor development through altering signal transduction, have been recently recognized as oncogenic factors in breast cancer.^82,83 This pathway significantly enhanced in breast cancer development, and contributes to cell survival, HER2 overexpression, poor differentiation, and tamoxifen resistance.^84–86 Since the KRAS/MAPK pathways promote the process of breast cancer, its direct regulator—miR-30c—may have important consequences in tumorigenesis. As reported, miR-30c contributed to malignancy formation through release of KRAS suppression and targeting KRAS/MAPK signaling in hereditary breast cancer.⁶⁶

Other factors involved in tumorigenesis

Several studies demonstrate that the miR-30 family could block nonattachment growth of breast tumor-initiating cells (BT-ICs). A target-based screening showed that miR-30 family regulated the expressions of apoptosis- and proliferation-related genes, such as anti-apoptotic protein AVEN and forkhead box protein 1 (FOXD1), which lead to inhibition of breast tumor progression and apoptosis, respectively.^23,87 Furthermore, ectopic overexpression of miR-30 significantly inhibited self-renewal and induced apoptosis in BT-ICs by silencing Ubc9 and ITGB3.⁵⁵ In vivo functional experiments also showed that miR-30 overexpression remarkably reduced tumor growth and lung metastasis, whereas the interference of miR-30 expression promoted tumorigenesis and migration of breast cancer.

Mechanisms of miR-30 family members in metastasis and invasion

Metastasis remains a significant challenge in the therapy and outcomes of breast cancer, and many studies suggest that it may be linked to dysregulation of miRNA functions. Indeed, miR-30 family members were identified in many studies as tumor suppressors that inhibit metastasis and invasion of breast cancer by targeting corresponding genes and pathways (Figure 3).

Figure 3.

miR-30 family members in metastasis and invasion. miR-30 family members act as tumor suppressor miRNAs by targeting TWF1, Ubc9, and ITGB3. miR-30a and miR-30c block EMT progression by downregulating MTDH and VIM, respectively, and thus inhibit tumor metastasis and invasion.

EMT

EMT, which sometimes caused by the dysregulation of miRNAs, frequently recognized as a key molecular step during tumor metastasis, and local or distant invasion.^88,89 Indeed, miR-30 family members are proved to regulate tumor metastasis and invasion through modulation of EMT. Aberrant miR-30c expression affected the expressions of EMT markers, such as E-cadherin, snail, and vimentin (VIM), and resulted in the suppression of EMT.⁸⁸ Moreover, miR-30c could suppress EMT and reduce cancer cell invasion through targeting cytoskeleton genes, Twinfilin 1 (TWF1) and VIM.⁶⁷ Similarly, upregulation of other miR-30 family members also reduced metastatic potential in cancer development. In a recent study, miR-30a was proved to inhibit the EMT-promoting migration of breast cancer by binding to the 3′-UTR of VIM, and lead to suppression of VIM expression and tumor invasion.²⁴

Interestingly, a major characteristic of EMT is to reduce E-cadherin expression and subsequently upregulate the expressions of mesenchymal markers (e.g. VIM), leading to the loss of cell-cell contact in epithelial cells which facilitates the local invasion and metastasis of tumor cells.⁹⁰ In this regard, reducing the expressions of VIM and other EMT promoters by miR-30 family members may be an effective way to suppress metastasis and invasion in epithelial tumors, especially aggressive breast cancer.

Other mechanisms

In addition to the suppression of EMT, miR-30 family members also targeted other various pathways and genes to suppress tumor metastasis and invasion. One study reported that miR-30a suppressed migration and invasion of breast cancer mediated by metadherin, a potent mediator in promoting the development of malignancies.¹⁶ Moreover, downregulation of miR-30a was proved to be associated with tumor hematogenous metastasis by targeting angiogenesis-specific delta-like ligand 4 (DLL4), which expression level was linked with nodal and distant metastasis.^91,92 Therefore, miR-30 family may serve a unique function in angiogenesis and metastasis of breast cancer.

miR-30 family members in therapeutic applications

Despite the development of multiple cancer treatments, surgical operation, chemotherapy, and radiation therapy are still prominent in breast cancer treatment, and one major problem in breast cancer postoperative treatment is generally recognized as drug resistance. According to different targets of drug resistance–induced recurrence and distal metastasis, we mainly focus on three drugs: tamoxifen, doxorubicin, and trastuzumab, which are commonly used in breast cancer therapy (Figure 4).

Figure 4.

miR-30 family members in drug resistance. miR-30c promotes paclitaxel- and doxorubicin-resistance by targeting TWF1-IL-11 pathway. miR-30c downregulates YWHAZ following the activation of MAPK pathway, resulting in doxorubicin-resistance. In addition, miR-30c facilitates tamoxifen resistance through reducing EGFR expression. miR-30b could induce G1 cell cycle arrest through targeting CCNE2 and following trastuzumab-resistance.

Estrogen receptor-α (ERα) and endocrinotherapy

Studies indicate that miR-30 family plays important roles in the acquisition of anti-estrogen resistance. ERα, expressed in almost 75% of breast cancer, is pivotal in the development and progression of breast cancer.⁹³ Tamoxifen, a selective ER regulator, is recognized as the first-line endocrine therapy that can significantly prolong the relapse-free and overall survival of ER-expressing breast cancer patients.^94,95 However, many ER-positive tumors that initially respond to tamoxifen eventually develop resistance with the continued administration in few years.⁹⁶ Studies have identified that miR-30c was positively correlated to ERα and negatively to epidermal growth factor receptor (EGFR); moreover, high expression levels of both miR-30a-3p and -30c could induce clinical benefits in tamoxifen treatment and prolong progression-free survival (PFS) in advanced ER-positive breast cancer patients.^69,97 Based on global testing and gene expression data, it was found that miR-30c and miR-30a-3p were both negatively associated with the “RAC1 cell motility signaling pathway” and its driving growth factor receptor (PDGFRa), and enhanced tamoxifen resistance in breast cancer cells.⁹⁸ Regarding these findings, miR-30 family may be novel therapeutic strategies to prevent the development of tamoxifen resistance or resensitize tumors to tamoxifen in ER-positive breast cancer patients.

Chemotherapy and chemoresistance

Adjuvant chemotherapy is effective to reduce metastatic recurrence for breast cancer patients after surgery. Unexpectedly, a considerable proportion of women suffer from recurrence or metastasis due to natural or acquired chemoresistance. Recently, chemoresistance was found correlated with miR-30 family members. As reported, the overexpression of miR-30c downregulated the MAPK pathway and resensitized breast cancer cells to doxorubicin by targeting tyrosine 3-monooxygenase/tryptophan 5-monooxygenaseactivation protein zeta polypeptide (YWHAZ).¹⁷ YWHAZ, which codes an anti-apoptotic protein 14-3-3ζ, is frequently reported to modulate MAPK pathways^17,99,100 and participate in tumor cell proliferation, apoptosis, and drug resistance.^101–104 Overexpression of YWHAZ could contribute to de novo chemoresistance and is permissive for metastatic recurrence in breast cancer cell lines,¹⁰¹ indicating that reducing YWHAZ expression by miR-30c may enhance chemotherapeutic efficiency or even reverse chemoresistance in some extent. Furthermore, upregulating the miR-30c expression can remarkably reduce the expression of cytoskeleton gene TWF1 and its downstream factor cytokine IL-11, which caused several breast cancer cells resensitized to paclitaxel and doxorubicin treatments.⁶⁸

HER2-positive breast cancer and targeted therapy

Trastuzumab (Herceptin), a humanized monoclonal antibody, was recently used to treat HER2-positive breast cancers by targeting HER2 and blocking its function.¹⁰⁵ More recently, miR-30b, -30a, and -30c have been identified that these miRNAs were all related with the trastuzumab response of breast cancer, and moreover, trastuzumab could increase the expression of miR-30b to induce G1 cell cycle arrest and cell growth inhibition by cyclin E2 (CCNE2).⁶⁵ Indeed, overexpression of cyclin E1 (CCNE1) was also found to enhance trastuzumab resistance.¹⁰⁶ Since CCNE1 and CCNE2 activate cyclin-dependent kinase 2 (CDK2) and thus initiate DNA synthesis, it is reasonable to consider that the miR-30 family may be a key factor for cell cycle check and apoptosis, and thus affect clinical outcomes of CCNE-mediated trastuzumab treatment in HER2-positive breast cancer patients.

miR-30 family members as prognosis biomarkers

Accumulating evidence suggests that some miRNAs that function as oncogenes or tumor suppressors play crucial roles in tumorigenesis and metastasis, and their expressions are correlated to clinical recurrence, metastases, and survival.^107–109 According to many studies, miR-30 family members were recognized as diagnostic and prognostic factors in lung cancer, breast cancer, chondrosarcoma, and prostate cancer (Table 3).^69,110–112

Table 3.

Clinical significance of miR-30 family in breast cancer.

miRNAs	Conclusions	Clinical applications	References
miR-30a	Clinicopathological analysis revealed that downregulation of miR-30a was significantly associated with lymph node metastasis.	Serve as a prognostic marker of tumor growth and metastasis in breast cancer.	Zhang et al.¹⁶
miR-30a	miR-30a expression was inversely correlated with prognosis in patients with IDC (invasive ductal carcinoma)	A tumor biomarker for predicting the outcome of breast cancer.	Cheng et al.²⁴
miR-30c	miR-30c and downstream targets VIM, TWF1, IL-11 are associated with tumor metastasis and clinical breast cancer outcomes.	Served as prognostic markers for clinical outcomes, and may become promising targets of invasive breast cancer.	Bockhorn et al.⁶⁷
miR-30c	miR-30a-3p and miR-30c were significantly associated with benefit of tamoxifen treatment and with longer PFS.	An independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer.	Rodriguez-Gonzalez et al.⁶⁹
miR-30e*	miR-30e* was identified as an independent protective prognostic factor in ESR1+/ERBB2- and ERBB2+ tumors, but not in ESR1-/ERBB2- tumors.	An independent subtype-specific prognostic marker in breast cancer	D’Aiuto et al.⁷⁰

TWF1: Twinfilin 1;VIM: vimentin; PFS: progression-free survival.

In a recent study, miR-30e* was found correlated with a favorable prognosis in ESR1+/ERBB2− breast tumors, and this protective effect on disease-specific survival was proved to be independent of other clinically relevant prognostic factors.⁷⁰ However, miR-30e* failed to affect the prognosis of patients with ESR1−/ERBB2− tumors, indicating the relation of miR-30e* expression to protective prognosis was subtype specific.⁷⁰ Moreover, miR-30c was discovered as an independent predictor for clinical benefit of tamoxifen therapy and PFS in advanced ER-positive breast cancer patients.⁶⁹ Similarly, lower expression of miR-30a was found associated with LNM, advanced stage, and shorter disease-free survival (DFS) in breast cancer patients.²⁴ All these findings further indicated the crucial roles of miR-30 family in breast cancer development, and the potential ability of these miRNAs served as promising factors for clinical prognosis of breast cancer.

Questions and prospectives

miR-30 family members, which shared the same seed sequence located near the 5′end, have different compensatory sequences located near the 3′end, which endow them with distinct biological behaviors in neoplastic transformation. Accordingly, despite the numerous studies on the relations between miR-30 family members and cancer progression, the differential behaviors of oncogenesis and tumor suppressor in various tumor development make it difficult to summary the functions of miR-30 family in all tumors. In this regard, future studies should be designed to identify the accurate function of each miR-30 family member in one specific tumor.

Although miR-30 family members play various roles both in tumorigenesis and suppression, they mainly act as tumor suppressors in breast cancer genesis, metastasis, and drug resistance, and even become anti-cancer predictive factors for DFS and LNM of breast cancer patients. More interestingly, miR-30e* was proved as a subtype-specific prognosis factor for ESR1/ERBB2 breast cancer,⁷⁰ suggesting that miR-30 family members may be subtype-specific factors for either prognosis or clinical treatment of breast cancer.

Conclusion

This review is focused on the roles of miR-30 family members in breast cancer: regulation of tumorigenesis, interference with tumor invasion and metastasis, and reversal of drug resistance. In addition, some miR-30 family members have independent protective effects on prognosis of breast cancer patients. We further elaborate the functions of different family members. Almost all of the miR-30 family members are involved in tumorigenesis, while miR-30b and miR-30c are proved to be able to alter drug resistance in breast cancer. In addition, miR-30a and miR-30c are more associated with EMT progression which has a highly positive correlation with tumor metastasis. Furthermore, miR-30e*, miR-30a, and miR-30c were identified as novel prognosis biomarkers for DFS and LNM of breast cancer patients.

Nevertheless, more studies are needed to explain the functions of the miR-30 family members, and miR-30 family members do act as promising biomarkers and therapeutic targets of breast cancer. Our understanding of the miR-30 family will accelerate the translation of these findings from in vitro to in vivo and bring a novel insight in diagnosis, prognosis, and molecular targeted therapy of breast cancer.

Footnotes

Acknowledgements

The authors thank Su-Yu Yang for useful discussions and helping in revision of this paper. Su-Jin Yang and Su-Yu Yang contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Funding

This study was funded by the National Natural Science Foundation of China (grant no. 81272470), the National key clinical specialist construction Programs of China (No. 2013[544]), Major Program of Natural Science Foundation of Jiangsu Province (No. BL2014090), Natural Science Foundation of Jiangsu Province (No. BK20151579), the Key Research Program for the Social Development of Jiangsu Province, China (BE2015718), the National Natural Science Foundation of China (grant no. 81602551).

References

Bushati

Cohen

SM.

microRNA functions. Annu Rev Cell Dev Biol 2007; 23: 175–205.

Huang

Jiang

Wang

. miR-5100 promotes tumor growth in lung cancer by targeting Rab6. Cancer Lett 2015; 362: 15–24.

Zhao

Lin

Zhu

. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/beta-catenin/BCL9 pathway. Cancer Res 2014; 74: 1801–1813.

Adams

Wali

Cheng

. miR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer. Cancer Res 2016; 76: 927–939.

Patel

Shah

Lee

. A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth. Oncotarget 2016; 7(14): 18295–18308.

Xie

miR-152 functions as a tumor suppressor in colorectal cancer by targeting PIK3R3. Tumour Biol 2016; 37(8): 10075–10084.

Emdad

Janjic

Alzubi

. Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness. Neuro Oncol 2015; 17: 419–429.

Jung

Zhang

Zhou

. Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology 2016; 63: 864–879.

Kong

Ferland-McCollough

Jackson

. microRNAs in cancer management. Lancet Oncol 2012; 13: e249–258.

10.

Baserga

Chen

. microRNA, cell cycle, and human breast cancer. Am J Pathol 2010; 176: 1058–1064.

11.

Herranz

Ruibal

Optical imaging in breast cancer diagnosis: the next evolution. J Oncol 2012; 2012: 863747.

12.

Wang

. Cyclin D1 induction of Dicer governs microRNA processing and expression in breast cancer. Nat Commun 2013; 4: 2812.

13.

Zhang

Liu

. MicroRNAs in the diagnosis and prognosis of breast cancer and their therapeutic potential (review). Int J Oncol 2014; 45: 950–958.

14.

Vilquin

Donini

Villedieu

. MicroRNA-125b upregulation confers aromatase inhibitor resistance and is a novel marker of poor prognosis in breast cancer. Breast Cancer Res 2015; 17: 13.

15.

Heinzelmann

Unrein

Wickmann

. MicroRNAs with prognostic potential for metastasis in clear cell renal cell carcinoma: a comparison of primary tumors and distant metastases. Ann Surg Oncol 2014; 21: 1046–1054.

16.

Zhang

Wang

Huo

. MicroRNA-30a suppresses breast tumor growth and metastasis by targeting metadherin. Oncogene 2014; 33: 3119–3128.

17.

Fang

Shen

Cao

. Involvement of miR-30c in resistance to doxorubicin by regulating YWHAZ in breast cancer cells. Braz J Med Biol Res 2014; 47: 60–69.

18.

Chang

Lee

. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 2008; 40: 43–50.

19.

Brennecke

Stark

Russell

. Principles of microRNA-target recognition. PLoS Biol 2005; 3: e85.

20.

Volinia

Galasso

Costinean

. Reprogramming of miRNA networks in cancer and leukemia. Genome Res 2010; 20: 589–599.

21.

Katzerke

Madan

Gerloff

. Transcription factor C/EBPα-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia. Blood 2013; 122: 2433–2442.

22.

Mahdavinezhad

Mousavi-Bahar

Poorolajal

. Evaluation of miR-141, miR-200c, miR-30b expression and clinicopathological features of bladder cancer. Int J Mol Cell Med 2015; 4: 32–39.

23.

Ouzounova

MicroRNA miR-30 family regulates non-attachment growth of breast cancer cells. BMC Genomics 2013; 14: 139.

24.

Cheng

Wang

Chang

. MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer. Breast Cancer Res Treat 2012; 134: 1081–1093.

25.

Zhang

Tang

Qin

. Role of microRNA 30a targeting insulin receptor substrate 2 in colorectal tumorigenesis. Mol Cell Biol 2015; 35: 988–1000.

26.

Hershkovitz-Rokah

Modai

Pasmanik-Chor

. MiR-30e induces apoptosis and sensitizes K562 cells to imatinib treatment via regulation of the BCR-ABL protein. Cancer Lett 2015; 356: 597–605.

27.

Martinez

Cazalla

Almstead

. miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc Natl Acad Sci USA 2011; 108: 522–527.

28.

Kong

Yan

. Estrogen regulates the tumour suppressor MiRNA-30c and its target gene, MTA-1, in endometrial cancer. PLoS ONE 2014; 9: e90810.

29.

Zhou

Xun

. microRNA-30c negatively regulates endometrial cancer cells by targeting metastasis-associated gene-1. Oncol Rep 2012; 27: 807–812.

30.

Che

Sun

Wang

. miR-30 overexpression promotes glioma stem cells by regulating Jak/STAT3 signaling pathway. Tumour Biol 2015; 36(9): 6805–6811.

31.

Chao

Kan

. The role of microRNA-30c in the self-renewal and differentiation of C6 glioma cells. Stem Cell Res 2015; 14: 211–223.

32.

Yang

Pan

Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression. Tumour Biol. Epub ahead of print 25 July 2015. DOI: 10.1007/s13277-015-3775-6.

33.

Liu

Effects of microRNA-30a on migration, invasion and prognosis of hepatocellular carcinoma. FEBS Lett 2014; 588: 3089–3097.

34.

Zhang

Liao

. miR-30c negatively regulates the migration and invasion by targeting the immediate early response protein 2 in SMMC-7721 and HepG2 cells. Am J Cancer Res 2015; 5: 1435–1446.

35.

Liu

Chen

Zhang

. RUNX3 regulates vimentin expression via miR-30a during epithelial-mesenchymal transition in gastric cancer cells. J Cell Mol Med 2014; 18: 610–623.

36.

Wang

Overexpression of microRNA-30b improves adenovirus-mediated p53 cancer gene therapy for laryngeal carcinoma. Int J Mol Sci 2014; 15: 19729–19740.

37.

Ryan

Elliott

. Amplification and overexpression of Hsa-miR-30b, Hsa-miR-30d and KHDRBS3 at 8q24.22-q24.23 in medulloblastoma. PLoS ONE 2009; 4: e6159.

38.

Zhang

Garnett

Creighton

. EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis. J Pathol 2014; 232: 308–318.

39.

Zhang

Yang

. Antitumor effects of pharmacological EZH2 inhibition on malignant peripheral nerve sheath tumor through the miR-30a and KPNB1 pathway. Mol Cancer 2015; 14: 55.

40.

Chen

Yang

. microRNA-30b inhibits cell invasion and migration through targeting collagen triple helix repeat containing 1 in non-small cell lung cancer. Cancer Cell Int 2015; 15: 85.

41.

Xia

Chen

Zhong

. Down-regulation of miR-30c promotes the invasion of non-small cell lung cancer by targeting MTA1. Cell Physiol Biochem 2013; 32: 476–485.

42.

Wang

. MicroRNA-30a promotes invasiveness and metastasis in vitro and in vivo through epithelial-mesenchymal transition and results in poor survival of nasopharyngeal carcinoma patients. Exp Biol Med 2014; 239: 891–898.

43.

Jia

Eneh

Ratnaparkhe

. MicroRNA-30c-2* expressed in ovarian cancer cells suppresses growth factor-induced cellular proliferation and downregulates the oncogene BCL9. Mol Cancer Res 2011; 9: 1732–1745.

44.

Shao

. Amplification and up-regulation of microRNA-30b in oral squamous cell cancers. Arch Oral Biol 2012; 57: 1012–1017.

45.

Poudel

Song

Jin

. Sulfuretin-induced miR-30C selectively downregulates cyclin D1 and D2 and triggers cell death in human cancer cell lines. Biochem Biophys Res Commun 2013; 431: 572–578.

46.

Huang

Yao

Zhang

. Hypoxia-induced downregulation of miR-30c promotes epithelial-mesenchymal transition in human renal cell carcinoma. Cancer Sci 2013; 104: 1609–1617.

47.

Esposito

Tornincasa

Pallante

. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab 2012; 97: E710–E718.

48.

Kumarswamy

Mudduluru

Ceppi

. MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. Int J Cancer 2012; 130: 2044–2053.

49.

Sousa

Nam

Petersen

. miR-30-HNF4gamma and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach. Gut 2015; 65(6): 914–924.

50.

Liu

Guo

. AEG-1 3′-untranslated region functions as a ceRNA in inducing epithelial-mesenchymal transition of human non-small cell lung cancer by regulating miR-30a activity. Eur J Cell Biol 2015; 94: 22–31.

51.

Yao

Liang

Huang

. MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology 2010; 51: 846–856.

52.

Zou

Ding

. MicroRNA-30a sensitizes tumor cells to cis-platinum via suppressing beclin 1-mediated autophagy. J Biol Chem 2012; 287: 4148–4156.

53.

Kao

Martiniez

Shi

. miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT. Oncogene 2014; 33: 2495–2503.

54.

Fuster

Llop

Dolz

. Adverse prognostic value of MYBL2 overexpression and association with microRNA-30 family in acute myeloid leukemia patients. Leuk Res 2013; 37: 1690–1696.

55.

Deng

Yao

. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene 2010; 29: 4194–4204.

56.

Krek

Grun

Poy

. Combinatorial microRNA target predictions. Nat Genet 2005; 37: 495–500.

57.

Wang

Tang

MiR-30a upregulates BCL2A1, IER3 and cyclin D2 expression by targeting FOXL2. Oncol Lett 2015; 9: 967–971.

58.

Zhou

Gong

Tan

. Urinary microRNA-30a-5p is a potential biomarker for ovarian serous adenocarcinoma. Oncol Rep 2015; 33: 2915–2923.

59.

Gaziel-Sovran

Segura

Di Micco

. miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell 2011; 20: 104–118.

60.

Wen

Zhao

. MiR-30a suppresses non-small cell lung cancer progression through AKT signaling pathway by targeting IGF1R. Cell Mol Biol 2015; 61: 78–85.

61.

Chen

Guo

Qiu

. MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer. Cancer Lett 2015; 362: 208–217.

62.

Dobson

Taipaleenmaki

. hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3. Cancer Cell Int 2014; 14: 73.

63.

Elson-Schwab

Lorentzen

Marshall

CJ.

MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PLoS ONE 2010; 5: e13176.

64.

Kang

. miR-30a suppresses breast cancer cell proliferation and migration by targeting Eya2. Biochem Biophys Res Commun 2014; 445: 314–319.

65.

Ichikawa

Sato

Terasawa

. Trastuzumab produces therapeutic actions by upregulating miR-26a and miR-30b in breast cancer cells. PLoS ONE 2012; 7: e31422.

66.

Tanic

Yanowsky

Rodriguez-Antona

. Deregulated miRNAs in hereditary breast cancer revealed a role for miR-30c in regulating KRAS oncogene. PLoS ONE 2012; 7: e38847.

67.

Bockhorn

Yee

Chang

. MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion. Breast Cancer Res Treat 2013; 137: 373–382.

68.

Bockhorn

Dalton

Nwachukwu

. MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nat Commun 2013; 4: 1393.

69.

Rodriguez-Gonzalez

Sieuwerts

Smid

. MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat 2011; 127: 43–51.

70.

D’Aiuto

Callari

Dugo

. miR-30e* is an independent subtype-specific prognostic marker in breast cancer. Br J Cancer 2015; 113: 290–298.

71.

Buffa

Camps

Winchester

. microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res 2011; 71: 5635–5645.

72.

Liu

Tang

Chen

. MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer. Oncotarget 2015; 6: 20070–20083.

73.

Shi

Wang

The role of MTDH/AEG-1 in the progression of cancer. Int J Clin Exp Med 2015; 8: 4795–4807.

74.

Jin

Chen

. MiR-30d induces apoptosis and is regulated by the Akt/FOXO pathway in renal cell carcinoma. Cell Signal 2013; 25: 1212–1221.

75.

Baonza

Freeman

Control of Drosophila eye specification by Wingless signalling. Development 2002; 129: 5313–5322.

76.

Furuya

Qadota

Chisholm

. The C. elegans eyes absent ortholog EYA-1 is required for tissue differentiation and plays partially redundant roles with PAX-6. Dev Biol 2005; 286: 452–463.

77.

Pandey

Wang

Tadjuidje

. Structure-activity relationships of benzbromarone metabolites and derivatives as EYA inhibitory anti-angiogenic agents. PLoS ONE 2013; 8: e84582.

78.

Liu

Han

Zhou

. The DACH/EYA/SIX gene network and its role in tumor initiation and progression. Int J Cancer 2016; 138(5): 1067–1075.

79.

Kenyon

Ranade

Curtiss

. Coordinating proliferation and tissue specification to promote regional identity in the Drosophila head. Dev Cell 2003; 5: 403–414.

80.

Zhang

Yang

Huang

. Transcriptional coactivator Drosophila eyes absent homologue 2 is up-regulated in epithelial ovarian cancer and promotes tumor growth. Cancer Res 2005; 65: 925–932.

81.

Blevins

Towers

Patrick

. The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets 2015; 19: 213–225.

82.

Yang

Cheon

Jung

. Interleukin-18 enhances breast cancer cell migration via down-regulation of claudin-12 and induction of the p38 MAPK pathway. Biochem Biophys Res Commun 2015; 459: 379–386.

83.

Wang

Zhou

. Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. Expert Opin Ther Targets 2015; 19: 577–587.

84.

Cerne

Stegel

Gersak

. KRAS rs61764370 is associated with HER2-overexpressed and poorly-differentiated breast cancer in hormone replacement therapy users: a case control study. BMC Cancer 2012; 12: 105.

85.

Booy

Henson

Gibson

SB.

Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 2011; 30: 2367–2378.

86.

Heckler

Thakor

Schafer

. ERK/MAPK regulates ERRgamma expression, transcriptional activity and receptor-mediated tamoxifen resistance in ER⁺ breast cancer. FEBS J 2014; 281: 2431–2442.

87.

Melzer

Fernandez

Bosser

. The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential. Cell Death Differ 2012; 19: 1435–1445.

88.

Zhong

Xia

Wang

. Low expression of microRNA-30c promotes invasion by inducing epithelial mesenchymal transition in non-small cell lung cancer. Mol Med Rep 2014; 10: 2575–2579.

89.

Rokavec

Oner

. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 2014; 124: 1853–1867.

90.

Vuoriluoto

Haugen

Kiviluoto

. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011; 30: 1436–1448.

91.

Huang

Zhang

. Down-regulated miR-30a in clear cell renal cell carcinoma correlated with tumor hematogenous metastasis by targeting angiogenesis-specific DLL4. PLoS ONE 2013; 8: e67294.

92.

Kontomanolis

Panteliadou

Giatromanolaki

. Delta-like ligand 4 (DLL4) in the plasma and neoplastic tissues from breast cancer patients: correlation with metastasis. Med Oncol 2014; 31: 945.

93.

Ariazi

Cordera

. Estrogen receptors as therapeutic targets in breast cancer. Curr Topic Med Chem 2006; 6: 181–202.

94.

Osborne

Schiff

Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011; 62: 233–247.

95.

Jordan

VC.

Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2003; 2: 205–213.

96.

Ramaswamy

Teng

. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res 2012; 72: 5048–5059.

97.

Osborne

Schiff

Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. Breast 2003; 12: 362–367.

98.

Meijer

van Agthoven

Bosma

. Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells. Mol Cancer Res 2006; 4: 379–386.

99.

Min

Liang

Zhang

. Multiple tumor-associated microRNAs modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2 signaling pathways. J Immunol 2013; 190: 2437–2446.

100.

Zhang

Luo

Ding

. MicroRNA-451 regulates p38 MAPK signaling by targeting of Ywhaz and suppresses the mesangial hypertrophy in early diabetic nephropathy. FEBS Lett 2012; 586: 20–26.

101.

Zou

. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat Med 2010; 16: 214–218.

102.

Chen

Chuang

Yang

. A novel function of YWHAZ/beta-catenin axis in promoting epithelial-mesenchymal transition and lung cancer metastasis. Mol Cancer Res 2012; 10: 1319–1331.

103.

Menon

Deng

Ruenauver

. Somatic copy number alterations by whole-exome sequencing implicates YWHAZ and PTK2 in castration-resistant prostate cancer. J Pathol 2013; 231: 505–516.

104.

Nishimura

Komatsu

Ichikawa

. Overexpression of YWHAZ relates to tumor cell proliferation and malignant outcome of gastric carcinoma. Br J Cancer 2013; 108: 1324–1331.

105.

Slamon

Leyland-Jones

Shak

. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–792.

106.

Scaltriti

Eichhorn

Cortes

. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci USA 2011; 108: 3761–3766.

107.

Sondermann

Andreghetto

Moulatlet

. MiR-9 and miR-21 as prognostic biomarkers for recurrence in papillary thyroid cancer. Clin Exp Metastasis 2015; 32: 521–530.

108.

Lonvik

Sorbye

Nilsen

. Prognostic value of the MicroRNA regulators Dicer and Drosha in non-small-cell lung cancer: co-expression of Drosha and miR-126 predicts poor survival. BMC Clin Pathol 2014; 14: 45.

109.

Kalogirou

Spahn

Krebs

. MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer. Int J Mol Sci 2013; 14: 21414–21434.

110.

Tang

Liang

Luo

. Downregulation of MiR-30a is associated with poor prognosis in lung cancer. Med Sci Monit 2015; 21: 2514–2520.

111.

Lin

Wang

. Association of SOX4 regulated by tumor suppressor miR-30a with poor prognosis in low-grade chondrosarcoma. Tumour Biol 2015; 36: 3843–3852.

112.

Kobayashi

Uemura

Nagahama

. Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget 2012; 3: 1455–1471.

The miR-30 family: Versatile players in breast cancer

Abstract

Keywords

Introduction

Overview of miR-30 family in tumors

Genomic location of miR-30 family members

miR-30 family members as tumor suppressor miRNAs

miR-30 family members as onco-miRNAs

Functions of miR-30 family members in tumorigenesis

Mediation of MTDH (metadherin)

Suppression of Eya2 (eyes absent 2)

Blocking of KRAS/MAPK pathway

Other factors involved in tumorigenesis

Mechanisms of miR-30 family members in metastasis and invasion

EMT

Other mechanisms

miR-30 family members in therapeutic applications

Estrogen receptor-α (ERα) and endocrinotherapy

Chemotherapy and chemoresistance

HER2-positive breast cancer and targeted therapy

miR-30 family members as prognosis biomarkers

Questions and prospectives

Conclusion

Footnotes

Acknowledgements

Declaration of conflicting interests

Ethical approval

Funding

References