The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Abstract

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

Keywords: breast cancer; endocrine resistance; exosomes; extracellular vesicles; targeted therapies.

Figure 1

Representation of the main mechanisms sustaining endocrine resistance mediated by estrogen receptor α (ERα). The structural domains of ERα contain the ligand-independent activation function (AF-1) in the amino-terminal region, a DNA-binding domain (DBD), and a carboxy-terminal hormone-binding domain (HBD), containing the ligand-dependent activation function (AF-2). In the classical ERα activation, estradiol binds to its cognate receptor in the cytoplasm, leading to dimerization, nuclear translocation and interaction with specific DNA sequences (ERE, estrogen responsive element) in target genes (ligand-dependent activation). The ERα can also bind to transcription factors such as activation protein 1 (Ap1) and specificity protein 1 (Sp1) activating gene target transcription (non-classical activation). ERα signaling activation can also occur through second messengers downstream of growth factor signaling pathways (ligand-independent activation). (a) Altered ERα expression including either loss of ERα or increased ERα expression. (b) Gain of function mutations in the ESR1 gene. The most characterized mutations within ERα were reported. The K303R somatic mutation, in the hinge domain, allows ERα to be more highly phosphorylated by Protein Kinase A (PKA) and Protein Kinase B (PKB/Akt), while the Y537N, Y537S, and D538G mutations, in the HBD/AF-2 domain, allow the receptor to be phosphorylated by Mitogen-activated protein kinase (MAPK), resulting in a ligand-independent constitutive activation of the receptor. (c) An increased bidirectional cross-talk between wild-type or mutated ERα and growth factor receptors (epidermal growth factor receptor-EGFR, the human epidermal growth factor receptor 2-HER2, the insulin-like growth factor receptor 1-IGFR 1) induces several downstream phosphorylation events that affect ERα activation, and an altered interaction of ER with coregulators affects ER transcriptional activity in a ligand-independent manner sustaining endocrine resistance. Growth factor signaling can also contribute to endocrine resistance diminishing ESR1 gene expression.

Figure 2

The proposed function of EVs secreted by breast cancer or stromal cells in endocrine treatment resistance. EVs, by transferring their cargo in sensitive breast cancer cells, can confer traits of hormonal resistance by inducing signaling pathways involved in survival, migration, invasion, epithelial mesenchymal transition (EMT), in sustaining the cancer stem cell-like (CSC) phenotype and escape from dormancy. EVs can reduce the bioavailability of anti-HER2 mAb and immune evasion promoting resistance to targeted therapy to overcome endocrine therapies’ failure. Finally, evaluation of the molecular cargo of circulating EVs has promising value to discover potential biomarkers to predict the therapeutic response in ER-positive breast cancer patients.