Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal
estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence
of AI resistance (AI(R)). Exosomes act as vehicles to engender cancer progression
and drug resistance. The goal of this work was to study exosome contribution in AI(R)mechanisms,
using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term
Estrogen Deprived) subline, modeling AI(R). We found that exosome secretion was significantly
increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited
a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis
revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment
of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated
proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators
in cancer, that are significantly mapped in "small GTPase-mediated signal transduction",
"protein transport" and "vesicle-mediated transport" Gene Ontology categories. Expression
of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence,
for the first time, that AI(R)breast cancer cells display an increased capability
to release exosomes, which may be associated with an enhanced Rab GTPase expression.
These data provide the rationale for further studies directed at clarifying exosome's
role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic
targets for the management of hormone-resistant breast cancers.
