Abstract
Simple SummaryTwo-thirds of breast cancer patients present an estrogen receptor–positive tumor at diagnosis, and the main treatment options for these patients are endocrine therapies such as aromatase inhibitors, selective modulators of estrogen receptor activity or selective estrogen receptor down-regulators. Although endocrine therapies have high efficacy in early-stage breast cancers, the failure of the therapeutic response to these hormonal treatments remains the major clinical challenge. Recently, extracellular vesicles (EVs) have emerged as a novel mechanism of drug resistance. Indeed, EVs isolated from tumor and stromal cells act as key messengers in intercellular communications able to propagate traits of resistance and/or educate the microenvironment to sustain a breast cancer resistant phenotype. Understanding the EV-mediated molecular mechanisms involved in hormonal resistance can provide the rationale for novel and effective treatment modalities and allow for the identification of potential biomarkers to monitor therapy response in ER-positive breast cancer patients.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.
Highlights
Breast cancers are heterogeneous and dynamic diseases classified into molecularly distinct subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), which influence the clinical outcomes and the therapeutic approaches [1]
These findings suggest the possibility that more aggressive breast cancers could release a large amount of vesicles, but the comparison between the amounts of circulating extracellular vesicles (EVs) at different stages of disease should be better defined and deserves more investigations
Sansone et al have provided data supporting the hypothesis that the horizontal transfer of mitochondrial DNA from EVs regulates escape from dormancy in hormonal therapy (HT)-resistant breast cancer leading to metastatic progression
Summary
Breast cancers are heterogeneous and dynamic diseases classified into molecularly distinct subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), which influence the clinical outcomes and the therapeutic approaches [1]. Estrogen binding to the receptor can activate different molecular mechanisms termed “nonclassical” ER-mediated transcriptional regulation [3,4,5] This occurs via ERE-independent signaling in which ER interacts with other transcription factors, such as activator protein-1 (AP-1), specificity protein 1 (Sp1) and nuclear factor-κB (NF-κB), modulating downstream gene expression [3,4]. Data from pre-clinical and clinical specimens’ studies indicate that EVs secreted from both tumor and stromal cells through their functional cargo (proteins, mRNAs, miRNAs, DNAs) contribute to breast cancer drug resistance, regulating several processes, including cell survival, epithelial–mesenchymal transition, a stem-like phenotype, education of the tumor microenvironment and drug metabolism [17,18]. Given the lack of standardized nomenclature and isolation protocols for a large family of vesicles, we will use the term EVs to refer to this heterogeneous population throughout this review
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