Angioregulatory microRNAs in breast cancer : Molecular mechanistic basis and implications for therapeutic strategies

Abstract

Background: Cancer-associated angiogenesis is a fundamental process in tumor growth and metastasis. A variety of signaling regulators and pathways contribute to establish neovascularization, among them as small endogenous non-coding RNAs, microRNAs (miRNAs) play prominent dual regulatory function in breast cancer (BC) angiogenesis.

Aim of review: This review aims at describing the current state-of-the-art in BC angiogenesis-mediated by angioregulatory miRNAs, and an overview of miRNAs dysregulation association with the anti-angiogenic response in addition to potential clinical application of miRNAs-based therapeutics.

Key scientific concepts of review: Angioregulatory miRNA-target gene interaction is not only involved in sprouting vessels of breast tumors but also, trans-differentiation of BC cells to endothelial cells (ECs) in a process termed vasculogenic mimicry. Using canonical and non-canonical angiogenesis pathways, the tumor cell employs the oncogenic characteristics such as miRNAs dysregulation to increase survival, proliferation, oxygen and nutrient supply, and treatment resistance. Angioregulatory miRNAs in BC cells and their microenvironment have therapeutic potential in cancer treatment. Although, miRNAs dysregulation can serve as tumor biomarker nevertheless, due to the association of miRNAs dysregulation with anti-angiogenic resistant phenotype, clinical benefits of anti-angiogenic therapy might be challenging in BC. Hence, unveiling the molecular mechanism underlying angioregulatory miRNAs sparked a booming interest in finding new treatment strategies such as miRNA-based therapies in BC.

Keywords: Angiogenesis; Angioregulatory microRNA; Anti-angiogenic therapeutics; Breast cancer; Vascular mimicry.

Graphical abstract

Fig. 1

Schematic representation of molecular mediators in BC angiogenesis. PI3K/AKT/mTOR/VEGF, MAPK, STAT3, and Notch are major angiogenesis pathways in BC. VEGFA is a key angiogenic factor that involves in BC angiogenesis. Soluble VEGF receptor-2 (sVEGFR-2), vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), Glioma-associated oncogene homolog1 protein (Gli1), Hedgehog (Hh), Growth factor (GF) epidermal growth factor (EGF), Angiopoietin-2 (Ang-2), extracellular signal-regulated kinases (ERK), mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK), Phosphoinositide 3-kinase (PI3K), Transforming growth factor-β (TGF-β), Estradiol (E2), intracellular domain of the notch protein (NICD), Extracellular domain (ECD), Janus kinase (JAK), signal transducer and activator of transcription (STAT), focal adhesion (FAK), PTCH1 (Patched 1), SMO (Smoothened).

Fig. 2

In silico prediction of major signaling pathways asscotiated with angioregulatory miRNAs in BC by miRPathDB v2.0. The results indicated that the majority of these miRNAs are invovled in ErbB (HER) and VEGFA/VEGFR2 signaling pathways. Hence, understanding VEGFA expression regulation by miRNAs would be valuble in unraveling precise mechanisms underlying BC angiogenesis.

Fig. 3

Anti-angiogenic and pro-angiogenic miRNAs in BC cells and tumor microenvironment. Angioregulatory miRNAs by modulating of angiogenesis-related targets could suppress or promote BC angiogenesis. Angiogenesis is a crucial step in metastasis and can facilitate tumor metastasis. Cancer cells and TME communication involved in BC angiogenesis. For instance, exosomal miRNAs such as miR-542-3p, miR-100 and miR-205 may regulate BC angiogenesis through macrophages, MSCs and CAFs respectively. MSC, mesenchymal stem cell; CAF, cancer-associated fibroblasts; TAM, tumor-associated macrophages; ECM, extracellular matrix; EC, endothelial cell.

Fig. 4

Angioregulatory miRNAs in VM. BC cells transdifferentiated to EC-like tumor cell. VM is the ability of forming de novo vascular networks in aggressive tumor cells, moreover vessel sprouting together with VM can support tumor growth. Angioregulatory miRNAs can promote or suppress this process in BC. EC, endothelial cells; VM, vasculogenic mimicry.

Fig. 5

HIF-1α/TWIST1/miRNA axis in VM. HIF-1α by binding to HRE can induce TWIST1 under hypoxia condition. Regulating TWIST1 expression by angioregulatory miRNA and Sunitinib can trigger VM. This phenomenon may be involved in anti-angiogenic therapy resistance. HIF-1α, hypoxia inducible factor 1 subunit alpha; HRE, hypoxia-response element; EC, endothelial cells; LncRNA, long non-coding RNA.

Fig. 6

MiR-21 is a key angioregulatory miRNA in anti-angiogeneic therapy response. MiR-21 is mostly reduced in response to anti-angiogenic effect of phytochemical drugs. Although, Resveratrol activates miR-21 expression, it can inhbite others angio-prmoting miRNAs in BC.

Fig. 7

Nanotherapeutics containing miRNAs or miRNA antagonists in BC therapy. Specefic delivery of nanotherapeutics such as RGD-conjugated liposome and AAN-RGD liposomes can inhibit tumor angiogenesis by simultanously targeting TME cells.