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).