Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Sep;39(3):837-886.
doi: 10.1007/s10555-020-09905-7.

Regulation of breast cancer metastasis signaling by miRNAs

Belinda J Petri  1 , Carolyn M Klinge  2
Affiliations
Review

Regulation of breast cancer metastasis signaling by miRNAs

Belinda J Petri et al. Cancer Metastasis Rev. 2020 Sep.

Abstract

Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in U.S. women. The invasion-metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules. The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment. Each of these processes is regulated by changes in gene expression. Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression. miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs). The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer. We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade. We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis. It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete.

Keywords: Breast cancer metastasis; EMT; TGFβ; miRNAs.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors declare that they have no competing interests.

Figures

Fig. 1:
Fig. 1:. A brief summary of miRNA biogenesis and aspects of regulation in breast cancer and metastasis.
The pathway and proteins involved are described in the test. The upregulation of ERα36 in breast cancer is reviewed in [72]; the regulation of SPRY2 is reviewed in [336]; and MYC upregulation of miR-9 in [752].
Fig. 2:
Fig. 2:. An overview of the metastatic process in breast cancer.
The overall metastatic pathway was recently reviewed in [87]. Purple-fill arrows indicate upregulation, open arrows indicate downregulation, and green arrows indicate stimulation. Growth factor, cytokine, signaling pathways are in blue.
Figure 3:
Figure 3:. TGFβ stimulation of EMT, angiogenesis, and stemness in breast cancer progression toward metastasis.
TGFβ binds TGFβ type I and II receptors and phosphorylates SMAD2 and SMAD3. SMADs 2/3 form a complex with SMAD4, translocate into the nucleus to bind HMGA2, a chromatin remodeling factor, and activate the transcription of SNAI1, SNAI2, ZEB1/2 and TWIST1. These transcription factors suppress CDH1 and increase VEGFA, in addition to regulating other genes in EMT (not shown). Canonical NOTCH signaling is initiated by interaction of ligands from one cell, e.g., Jagged (JAG1, JAG2), Delta-like (DLL1,2,3,4) and cognate NOTCH (NOTCH1,2,3,4,5) receptors on adjacent cells. The interaction activates cleavage of NOTCH receptor(s) by ADAM10 or ADAM17. γ-secretase cleavage releases NOTCH intracellular domain (NICD) that goes to the nucleus and interacts with RBPJ and MAML1 (Mastermind Like Transcriptional Coactivator 1) as a coactivator to stimulate gene transcription, including by interaction with NFκB. NICD also interacts with SMAD3 to regulate gene transcription. The indicated miRNAs and targets in this pathway are summarized in Tables 1–3.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vieira AF, & Schmitt F (2018). An Update on Breast Cancer Multigene Prognostic Tests—Emergent Clinical Biomarkers. [Review]. Front Med (Lausanne), 5(248), doi:10.3389/fmed.2018.00248. - DOI - PMC - PubMed
    1. Waks AG, & Winer EP (2019). Breast Cancer Treatment: A Review. JAMA, 321(3), 288–300, doi:10.1001/jama.2018.19323. - DOI - PubMed
    1. van Hellemond IEG, Geurts SME, & Tjan-Heijnen VCG (2018). Current Status of Extended Adjuvant Endocrine Therapy in Early Stage Breast Cancer. Current Treatment Options in Oncology, 19(5), 26, doi:10.1016/j.ctrv.2017.02.005 - DOI - PMC - PubMed
    1. Nourmoussavi M, Pansegrau G, Popesku J, Hammond GL, Kwon JS, & Carey MS (2017). Ovarian ablation for premenopausal breast cancer: A review of treatment considerations and the impact of premature menopause. Cancer Treatment Reviews, 55, 26–35, doi:10.1016/j.ctrv.2017.02.005 - DOI - PubMed
    1. Mathew A, & Davidson NE (2015). Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer. The Breast, 24, S120–S125, doi:10.1016/j.breast.2015.07.027. - DOI - PubMed

Publication types