3.2.3. Oncosterone is a ligand and a modulator of nuclear receptors.
Glucocorticoid receptor (GR) and oxysterol receptors LXR have been identified as oncosterone receptors. Oncosterone was shown to activate the nuclearization of GR in MDA-MB231 TN BC cells as observed with cortisol. Oncosterone was found to antagonize cortisol in its stimulation of the expression of two GR-dependent SGK1 and MKP1 genes. Gene reporter assays further confirmed that oncosterone did not modulate other oxysterol receptors such as RORs or FXR (Voisin et al., 2017), and binding assays showed that oncosterone interacted with LXRs and GR. GR knock down in BC cell lines induced a loss of the proliferative effects of oncosterone. A similar effect was also observed with GR ligands such as mifepristone (RU38486) and dexamethasone showing that GR mediates oncosterone mitogenicity. Structural differences between cortisol and oncosterone are key elements that drive GR activation differently in terms of gene regulation and cell proliferation. This suggests that conformational modifications of GR complexes will affect differently the recruitment of co-regulators, GR dimerization states (Kadmiel & Cidlowski, 2013; Vandewalle, Luypaert, De Bosscher & Libert, 2018) and even GR heterodimerization with other nuclear receptors (De Bosscher, Desmet, Clarisse, Estebanez-Perpina & Brunsveld, 2020).
In contrast, the LXR knock down did not affect OCDO-mediated BC cell proliferation (Voisin et al., 2017). Since LXR was found to control 27HC invasiveness, it was postulated that LXR could mediate the pro-invasive effects of oncosterone. Further investigations will be required to show that genetic and pharmacological inhibition of LXR can block the effects of oncosterone. These observations, in addition to the links that have already established between GR, glucocorticoids and BC (Kanai et al., 2020; Obradovic et al., 2019; Perez Kerkvliet et al., 2020; Tonsing-Carter et al., 2019), highlight the pharmacological interest of GR targeting for the control of BC development. The discovery of oncosterone as an endogenous GR ligand in BC will add a new rational to consider the implication of GR in BC development. Together these data underline the pharmacological importance of GR and LXR as effector of oncosterone and give a new rational for the targeted therapy of BC (Fig 3).