The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

SIMPLE SUMMARY: Two-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. 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.