Exosomal lncRNAs as regulators of breast cancer chemoresistance and metastasis and their potential use as biomarkers

Abstract

Breast cancer is the most common cancer in women and the leading cause of female deaths by cancer in the world worldwide. Hence, understanding the molecular mechanisms associated with breast cancer development and progression, including drug resistance and breast cancer metastasis, is essential for achieving the best management of breast cancer patients. Cancer-related long noncoding RNAs have been shown to be involved in the regulation of each stage of breast cancer progression. Additionally, exosomes are extracellular microvesicles that are central to intercellular communication and play an important role in tumorigenesis. Exosomes can be released from primary tumor cells into the bloodstream and transmit cellular signals to distant body sites. In this work, we review the findings regarding the cellular mechanisms regulated by exosomal lncRNAs that are essentials to chemoresistance development and metastasis of breast cancer. Likewise, we evaluate the outcomes of the potential clinical use of exosomal lncRNAs as breast cancer biomarkers to achieve personalized management of the patients. This finding highlights the importance of transcriptomic analysis of exosomal lncRNAs to understand the breast cancer tumorigenesis as well as to improve the clinical tests available for this disease.

Keywords: breast cancer; cancer biomarkers; chemoresistance; exosomes; lncRNA; metastasis.

Figure 1

Exosomal lncRNAs regulate drug resistance. The diagram shows how the effect of some lncRNAs released by BC cells, mediated by exosomes, can promote drug resistance through different cell pathways, including in many cases the sponging of miRNAs. The chemoresistance to each specific drug can be modulated by more than one exosomal lncRNA. HMGB3, high mobility group box 3; VASP, vasodilator-stimulated phosphoprotein; Rap 1, Ras-related protein 1; CXCL12, C-X-C motif chemokine ligand 12.

Figure 2

Exosomal lncRNAs are associated to many oncogenic pathways. The illustration shows the effect of some exosomal lncRNAs in the regulation of several cell pathways to induce angiogenesis, metastasis, drug resistance, etc. HUVECs, human umbilical vein endothelial cells; VASP, vasodilator-stimulated phosphoprotein; Rap 1, Ras-related protein 1; BMECs, brain microvascular endothelial cells; BBB, blood-brain barrier; PKM, pyruvate kinase muscle M1/M2.

Figure 3

Utility of exosomal lncRNAs as biomarkers of BC. It is outlined how patients with BC would have a peripheral blood sample taken, from which the plasma would be isolated, and the exosomes purified to be analyzed and measure the levels of their components, such as proteins or nucleic acids, including lncRNAs. The levels of exosomal lncRNAs can be measured and used as diagnostic, prognostic, metastatic and drug resistance biomarkers for BC patients.