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Table 1 Summary of miRNAs involved in regulating autophagy in human breast cancer (n = 41)

From: Regulation of autophagy by microRNAs in human breast cancer

Roles of miRNAs in regulating autophagy and tumorigenesis miRNAs Downstream targets (Affected autophagy steps) Study designs (Data source/cell lines/sample size, n) Study summary References
Promote both tumorigenesis and autophagy miR-23a In vitro secondary cell lines (MDA-MB-231, MDA-MB-453, T47D, SKBR3, BT549, MCF-10A and MCF-7); in vivo female Balb/c nude mice study (n = unclear for each group) Overexpression of miR-23a downregulated (p < 0.05) XIAP expression and this promoted autophagy and breast cancer tumorigenesis in vitro and in vivo [96]
miR-23b-3p In vitro secondary cell lines (MCF-7, ZR-75-1 and HCC1428); in vivo female Balb/c nude or NSG/NOD mice study (n = 4 for each group) Downregulation of SLC6A14 by miR-23b-3p caused increased influx of acidic amino acids in the endocrine therapy resistant breast cancer cells and this promoted autophagy and tumorigenesis [35]
miR-126 Clinical sampling (breast cancer patients = 106); in vitro secondary cell lines (MCF-7 and MDA-MB-231); in vivo female Balb/c nude mice study (n = 9 for each group) Overexpression of miR-126 downregulated IRS/Glut-4 signaling pathway and activated AMPK/autophagy pathway to promote tumorigenesis [86]
miR-638 In vitro secondary cell lines (KYSE450 ESCC and MCF-7); clinical sampling (breast cancer samples = 24, esophageal cancer tissues = 66) Upregulation of miR-638 would significantly downregulate (p < 0.05) DACT3 expression, which then promoted autophagy and tumorigenesis in both breast and esophageal cancers [81]
Promote autophagy but suppress tumorigenesis miR-125b-5p In vitro secondary cell lines (MCF-7); in vivo female Balb/c nude mice study (n = 6 for each group) MiR-125b-5p negatively regulated PAD2 (p < 0.05) and this sensitized the breast cancer cells to tamoxifen and docetaxel treatment by accelerating apoptosis and autophagy [66]
Suppress autophagy but promote tumorigenesis miR-20a Online clinical data (breast cancer = 694, normal = 83); clinical sampling (n = 30 for cancer or normal tissues); in vitro secondary cell lines (MDA-MB-231 and MCF-7); in vivo female Balb/c nude mice study (n = 12 for each group) miR-20a level was negatively correlated to BECN1, ATG16L1 and SQSTM1 expression level. Elevated miR-20a increased DNA mutation and tumorigenesis by decreasing autophagy activities [74]
miR-21 In vitro secondary cell line (MCF-7) Knockdown of miR-21 would enhance autophagy and improve breast cancer cells sensitivity to tamoxifen and fulvestrant by inhibiting PI3K/AKT/mTOR pathway [75]
  miR-25 In vitro secondary cell lines (MCF-7 and MCF-10A); in vivo female NOD/SCID mice (n = 6 for control or treated group) Upregulation of miR-25 reduced autophagy by reducing ULK1 expression (p < 0.05). This led to chemoresistance [68]
Suppress autophagy but promote tumorigenesis miR-96-5p In vitro secondary cell lines (MDA-MB-231, MCF-7, BT-549, HS578T, T47D, ZR-75-1 and MCF-10A) Overexpression of miR-96-5p significantly suppressed (p < 0.05) autophagy and apoptosis, and increased tumorigenesis [83]
miR-137 In vitro secondary cell lines (SKBR3, MCF-7 and MDA-MB-231) Overexpression of miR-137 significantly (p < 0.05) apoptosis and autophagy and promoted cancer cells tumorigenesis [99]
miR-221 In vitro secondary cell lines (MDA-MB-231, MCF-7, T47D, ZR-751, SKBR-3 and HMEC); in vivo athymic female mice (n = 5 for each group) Elevation of miR-221 downregulated beclin-1 (p < 0.05) in vitro and in vivo. This caused reduced autophagy but increased tumorigenesis and cancer aggressiveness [76]
miR-224-5p Clinical sampling (metastatic breast cancer = 30, non-metastatic breast cancer = 35, normal control = 25); in vitro secondary cell lines (MDA-MB-231 and MCF-7) Introduction of miR-224-5p suppressed autophagy by reducing Smad4 expression (p < 0.05). High miR-224-5p level was found in metastatic breast cancer patients than normal control or patients with non-metastatic lesions [101]
miR-486-5p In vitro secondary cell lines (MCF-7 and MDA-MB-231) Upregulation of miR-486-5p would downregulate PTEN expression (p < 0.05) and autophagy but enhanced AKT signaling pathway [56]
Suppress autophagy but promote tumorigenesis miR-638 Case–control (breast cancer or normal control, each had 47 samples); bioinformatics target prediction Downregulation of miR-638 might be associated with good disease prognosis and slow disease prognosis by increasing autophagy activity [79]
Suppress both autophagy and tumorigenesis Let-7a Un-reported In vitro secondary cell line (MDA-MB-231) Overexpression of Let-7a significantly (p < 0.05) increased apoptosis, reduced autophagy, and cell proliferation in vitro [102]
miR-20a
miR-20b
Clinical sampling (breast cancer tissues and normal tissues = 19); in vitro secondary cell lines (MCF-7, MCF-10A and MDA-MB-231) Overexpression of miR-20a and miR-20b suppressed (p < 0.05) autophagy and tumorigenesis [72]
miR-26b Clinical sampling (breast cancer tissues and normal tissues = 3); in vitro secondary cell line (MCF-7) Increased expression of miR-26b downregulated DRAM1 protein expression in breast cancer cell and this reduced autophagy and sensitized cancer cells to irradiation [92]
miR-27a In vitro secondary cell lines (MDA-MB-231 and MCF-7) Introduction of antagonist of miR-27a increased (p < 0.05) LC3-II and p62 expression in vitro, increased autophagy and chemoresistance [82]
Suppress both autophagy and tumorigenesis miR-101 In vitro secondary cell line (MCF-7) Overexpression of miR-101 downregulated STMN1, RAB5A and ATG4D. This inhibited autophagy and promoted tamoxifen (4-OHT) induced cells apoptosis [80]
  miR-107 Clinical sampling (breast cancer patients = 62); in vitro secondary cell lines (MDA-MB-231, MDA-MB-453, MCF-10A and MCF-7); in vivo female Balb/c nude mice study (n = 5 for each group) In breast cancer tissues and cell lines, miR-107 was downregulated (p < 0.01) and this was associated with increased tumorigenicity. Overexpression of miR-107 downregulated HMGB1 in vitro and in vivo and inhibited autophagy [36]
  miR-129-5p In vitro secondary cell line (MCF-7) Upregulation of miR-120-5p significantly suppressed (p < 0.05) HMGB1 expression. This led to autophagy downregulation and increased chemosensitivity against taxol [61]
  miR-200c Clinical sampling (breast cancer patients = 35); in vitro secondary cell lines (MDA-MB-231, BT549, BT474, MCF-10A and MCF-7) Ectopic expression of miR-200c downregulated UBQLN1 and this blocked radiation-induced autophagy and sensitized cancer cells to radiotherapy [93]
Suppress both autophagy and tumorigenesis miR-489 In vitro secondary cell line (T47D, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-361, Hs578T and ZR-75-1); in vivo athymic female mice (n = 5 for each group); clinical sampling (breast cancer patients = 14) In vitro and in vivo findings suggested that upregulation of miR-489 downregulated ULK1 and LAPTM4B, which then suppressed autophagy and increased cancer cells sensitivity towards doxorubicin [37]
  miR-567 Clinical sampling (breast cancer tissues = 98); in vitro secondary cell lines (SKBR3 and BT474); in vivo male Balb/c nude mice study (n = 4 for each group) Introduction of miR-567 downregulated ATG5 expression in vitro and in vivo, and this suppressed autophagy and sensitized cancer cells to trastuzumab [78]
  miR-1275 Clinical sampling divided into 3 cohorts (breast cancer samples = 161, normal tissues = 127); in vitro secondary cell lines (MDA-MB-231 and MCF-7); in vivo Balb/c nude female mice (n = 6 for each group) Overexpression of miR-1245 would downregulate ATG7 and ULK1 in vitro and in vivo, which then suppressed autophagy and tumorigenesis. Downregulation of miR-1275 by circCDYL in breast cancer patients led to poor survival [69]
Suppress both autophagy and tumorigenesis miR-30c-1
miR-149
miR-611
miR-615-5p
miR-659
miR-636
miR-638
miR-659
miR-675
miR-1303
miR-1308
miR-1908
miR-1914
miR-1915
miR-2861
miR-3184
miR-4292
miR-4259
In vitro secondary cell line (MDA-MB-231) Introduction of BIK interference would result in the upregulation of a number of autophagy-regulating miRNAs which were shown to regulate several key autophagy-related proteins like ULK1/2, LC3-II and MAPK3 [67]
  1. A total of 41 miRNAs from 26 published in vitro, in vivo and clinical studies were included in this review to discuss their roles in modulating autophagy in human breast cancer and to explore how does this influence the disease development and treatment response. 30 miRNAs were reported to suppress both autophagy and breast cancer tumerigenicity and these include let-7a [102], miR-20a and miR-20b [72], miR-26b [92], miR-27a [82], miR-101 [80], miR-107 [36], miR-129-5p [61], miR-200c [93], miR-489 [37], miR-567 [78], miR-1275 [69], and miR-30c-1, miR-149, miR-611, miR-615-5p, miR-659, miR-636, miR-638, miR-659, miR-675, miR-1303, miR-1308, miR-1908, miR-1914, miR-1915, miR-2861, miR-3184, miR-4292 and miR-4259 [67]. Four miRNAs which were shown to enhance both autophagy and breast cancer progression include miR-23a [96], miR-23b-3p [35], miR-126 [86] and miR-638 [81]. Nine miRNAs were found to suppress autophagy but enhance breast cancer development and these miRNAs include miR-20a [74], miR-21 [75], miR-25 [68], miR-96-5p [83], miR-137 [99], miR-221 [76], miR-224-5p [101], miR-486-5p [56] and miR-638 [79]. One miRNA was shown to promote autophagy and suppress breast cancer tumerigenicity and this miRNA is miR-125b-5p [66]. Out of all these miRNAs, miR-20a was found to suppress both autophagy and tumorigenesis in a study [72] but in another study [74], miR-20a was said to promote cancer progression despite it suppressed cellular autophagy. Another miRNA which was shown to have different overall effects on autophagy regulation in breast cancer is miR-638, in which it was demonstrated to accelerate both autophagy and tumorigenesis in a study [81] but in another case–control study [79], miR-638 was shown to inhibit autophagy and promote breast cancer progression
  2. Upregulation; Downregulation