Dysregulation of MicroRNAs in Breast Cancer and Prognosis
Dysregulation of MicroRNAs in Breast Cancer and Prognosis
In cancer, miRNAs play a role in oncogenesis, metastasis, and resistance to various therapies and can be classified as oncogenes (oncomirs) or tumor-suppressor genes. Additionally, both pro-metastatic ('metastamiRs') and metastasis-suppressor miRNAs can be identified.
Many miRNA genes are located in genomic regions involved in chromosomal alterations. Chromosomal regions encompassing oncogenic miRNAs may be amplified, resulting in increased expression of the oncomir. Tumor-suppressive miRNAs could reside in fragile sites characterized by deletions or mutations, leading to reduced levels of these miRNAs. An overview of the most prominent miRNAs involved in the pathogenesis of breast cancer is depicted in Table 1 and Table 2.
Examples of breast oncomirs are miR-10b, miR-21, miR-155, miR-373, and miR-520c. (See Table 1 and list of abbreviations for miRNA targets.) OncomiRs exert their oncogenic activity by targeting tumor-suppressor genes and activating oncogenic transcription factors.
MiR-10b targets HOXD10, thereby promoting cell migration and invasion. miR-21 has been reported to be associated with invasive and metastatic breast cancer and regulates epithelial-to-mesenchymal transition (EMT) and HIF1A in breast cancer stem cell-like cells. It also inhibits various tumor-suppressor proteins. MiR-155 suppresses SOCS1 both in vivo and in vitro, and upregulation results in proliferation of MCF7 cells. FOXO3 was identified as another miR-155 target, whose inhibition leads to enhanced cell survival and tumor growth. The expression of miR-373 and -520c, which target CD44, is associated with metastasis, invasion, and migration.
Tumor-suppressor miRNAs exhibit a lower expression in cancer cells and suppress oncogene expression, thereby controlling cellular differentiation. In regard to the global downregulation of miRNAs in cancer, it is worth mentioning that the majority of miRNAs have a tumor-suppressive function, some of which exhibit anti-metastatic properties as well. (See Table 2 and list of abbreviations for miRNA targets).
MiR-125b, which targets erythropoietin (EPO) and its receptor (EPOR) as well as ERBB2, is found to be one of the most downregulated miRNAs in breast cancer. MiR-205 regulates HMGB3 and its ectopic expression significantly inhibits cell proliferation and promotes apoptosis in breast cancer. Jiang and colleagues revealed how expression of the miR-17-92 cluster in triple-negative breast cancer (TNBC) was associated with significantly reduced metastasis. miR-206 inhibits cell proliferation, migration, and invasion by targeting cyclin D2 and Cx43.
Certain tumor-suppressive miRNAs have an inhibitory role in the metastasis cascade. For example, the miR-200 family regulates EMT via E-cadherin expression by targeting several EMT inducers. MiR-146b inhibits nuclear factor kappa B (NF-κB)-dependent interleukin (IL)-6 expression, which is associated with impaired survival and metastasis of cancer cells. Decreased expression of miR-126 was seen in a variety of human cancers, and restoration of expression reduced metastatic endothelial recruitment and angiogenesis. MiR-335 is known to target several metastasis-associated genes (for example, SOX4 and TNC). Finally, independent studies have reported the pleiotropic actions of miR-31 on breast cancer metastasis and its ability to suppress multiple steps of the invasion-metastasis cascade, by targeting RhoA and WAVE3.
The action of certain miRNAs is dependent upon cellular or environmental context and results in both tumor-suppressive and -promoting roles. This could in part explain possible inconsistent outcomes from distinct miRNA-examining studies.
As described above, miR-146 exerts its tumor-suppressive action through negative regulation of NF-κB signaling. However, an additional target is the pro-apoptotic DNA repair enzyme BRCA1. MiR-29 stimulates metastasis and EMT by suppressing the cell-adhesion molecule peroxidasin homologue but is also capable of restraining cancer progression by targeting proliferation-inducing oncogenes, suppressing DNA methylation of tumor-suppressor genes, and increasing chemosensitivity. Although most data support an oncogenic function for miR-373 and -520c, a recent study reported this miR-family as a tumor suppressor in estrogen receptor (ER)-negative breast cancer.
MicroRNAs and Breast Cancer
The Role of MicroRNAs in Breast Cancer Biology and Metastasis
In cancer, miRNAs play a role in oncogenesis, metastasis, and resistance to various therapies and can be classified as oncogenes (oncomirs) or tumor-suppressor genes. Additionally, both pro-metastatic ('metastamiRs') and metastasis-suppressor miRNAs can be identified.
Many miRNA genes are located in genomic regions involved in chromosomal alterations. Chromosomal regions encompassing oncogenic miRNAs may be amplified, resulting in increased expression of the oncomir. Tumor-suppressive miRNAs could reside in fragile sites characterized by deletions or mutations, leading to reduced levels of these miRNAs. An overview of the most prominent miRNAs involved in the pathogenesis of breast cancer is depicted in Table 1 and Table 2.
Oncogenic MicroRNAs and 'MetastamiRs'
Examples of breast oncomirs are miR-10b, miR-21, miR-155, miR-373, and miR-520c. (See Table 1 and list of abbreviations for miRNA targets.) OncomiRs exert their oncogenic activity by targeting tumor-suppressor genes and activating oncogenic transcription factors.
MiR-10b targets HOXD10, thereby promoting cell migration and invasion. miR-21 has been reported to be associated with invasive and metastatic breast cancer and regulates epithelial-to-mesenchymal transition (EMT) and HIF1A in breast cancer stem cell-like cells. It also inhibits various tumor-suppressor proteins. MiR-155 suppresses SOCS1 both in vivo and in vitro, and upregulation results in proliferation of MCF7 cells. FOXO3 was identified as another miR-155 target, whose inhibition leads to enhanced cell survival and tumor growth. The expression of miR-373 and -520c, which target CD44, is associated with metastasis, invasion, and migration.
Tumor-suppressive and Metastasis-suppressive MicroRNAs
Tumor-suppressor miRNAs exhibit a lower expression in cancer cells and suppress oncogene expression, thereby controlling cellular differentiation. In regard to the global downregulation of miRNAs in cancer, it is worth mentioning that the majority of miRNAs have a tumor-suppressive function, some of which exhibit anti-metastatic properties as well. (See Table 2 and list of abbreviations for miRNA targets).
MiR-125b, which targets erythropoietin (EPO) and its receptor (EPOR) as well as ERBB2, is found to be one of the most downregulated miRNAs in breast cancer. MiR-205 regulates HMGB3 and its ectopic expression significantly inhibits cell proliferation and promotes apoptosis in breast cancer. Jiang and colleagues revealed how expression of the miR-17-92 cluster in triple-negative breast cancer (TNBC) was associated with significantly reduced metastasis. miR-206 inhibits cell proliferation, migration, and invasion by targeting cyclin D2 and Cx43.
Certain tumor-suppressive miRNAs have an inhibitory role in the metastasis cascade. For example, the miR-200 family regulates EMT via E-cadherin expression by targeting several EMT inducers. MiR-146b inhibits nuclear factor kappa B (NF-κB)-dependent interleukin (IL)-6 expression, which is associated with impaired survival and metastasis of cancer cells. Decreased expression of miR-126 was seen in a variety of human cancers, and restoration of expression reduced metastatic endothelial recruitment and angiogenesis. MiR-335 is known to target several metastasis-associated genes (for example, SOX4 and TNC). Finally, independent studies have reported the pleiotropic actions of miR-31 on breast cancer metastasis and its ability to suppress multiple steps of the invasion-metastasis cascade, by targeting RhoA and WAVE3.
Context-dependent MicroRNAs
The action of certain miRNAs is dependent upon cellular or environmental context and results in both tumor-suppressive and -promoting roles. This could in part explain possible inconsistent outcomes from distinct miRNA-examining studies.
As described above, miR-146 exerts its tumor-suppressive action through negative regulation of NF-κB signaling. However, an additional target is the pro-apoptotic DNA repair enzyme BRCA1. MiR-29 stimulates metastasis and EMT by suppressing the cell-adhesion molecule peroxidasin homologue but is also capable of restraining cancer progression by targeting proliferation-inducing oncogenes, suppressing DNA methylation of tumor-suppressor genes, and increasing chemosensitivity. Although most data support an oncogenic function for miR-373 and -520c, a recent study reported this miR-family as a tumor suppressor in estrogen receptor (ER)-negative breast cancer.
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