Fig. 1

Schematic representation of hormonal therapy actions at cellular and systemic level. Androgen and estrogen signaling can target multiple organs to regulate the expression of key coronavirus disease (COVID-19)-related genes, like the angiotensin-converting enzyme 2 (ACE2), the transmembrane protease, serine 2 (TMPRSS2), and the neuropilin-1 (NRP1) gene. While activation of the androgen receptor (AR) promotes the expression of these genes, facilitating the infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), estrogen receptor (ER) can inhibit ACE2 expression, lowering the chances of the virus accessing target cells and possibly restraining COVID-19 severity. Breast cancer patients are mostly treated with hormonal therapies that include tamoxifen, fulvestrant and aromatase inhibitors (AIs). AIs block estrogens conversion from androgens by inhibiting the catalytic activity of aromatase, an enzyme from the cytochrome P450 group. Fulvestrant leads to ER degradation through the proteasome. Patients treated with AIs and fulvestrant, may exhibit an increased risk of hospitalization by COVID-19 because estrogens lowering and the impossibility of acting through the ER respectively hinder protection. On the opposite, tamoxifen can exert a protective role through various mechanisms, including agonism on ER signaling, impairment of lysosomal acidification, alteration of free sex hormones availability via increased production of the sex hormone binding globulin (SHBG) which would alter the expression of genes associated with COVID-19 susceptibility, binding and modulation of Sigma-1 receptor (Sig-1R) involved in several intracellular processes.