The role of VAV3 in resistance to breast cancer endocrine therapy

Abstract

[EN] Breast cancer (BC) is the most commonly occurring cancer in women and the most prevalent cancer overall. Indeed, data indicate that 1 in 8-10 women will suffer from it throughout their lives and 30% of BC patients will die from this disease. In this project, we will focus on ER+ (oestrogen receptor-positive) BC, which comprises around 70% of BC cases. These patients usually present a positive prognosis, but the major clinical problem of this subtype is that some patients develop resistance to endocrine therapy (ET), and eventually relapse, which significantly affects their survival.

Among others, VAV3, a guanine nucleotide exchange factor (GEF) for small GTP-binding proteins (mainly, for Rho and Rac families), has been suggested as a controller of ET resistance. In this project, we have further characterized the expression and protein levels of VAV3 in patients' public databases as well as in breast cancer in vitro models, discovering that it is enriched particularly in the ER+ samples. Nevertheless, similar expression levels were found in MCF-7 cells and an in vitro model of ET resistance derived from them (LTED cells). In addition, short hairpin RNA technology was previously used for VAV3 silencing in the mammalian cells of interest to investigate its role in the ET resistance setting (Aguilar et al., 2014). Consequently, we have developed lentiviral particles to silence VAV3 expression in MCF-7 and LTED cells and, in the future, study in detail the molecular mechanisms controlled by VAV3 driving ET resistance. Thus, our research highlights the importance of VAV3 in ER+ breast tumours and contributes with tools to further study its roles in ET resistance, in which VAV3 may be used as a relevant prognostic/predictive biomarker and/or a future therapeutic target.