3.2.2. Oncosterone is produced by the 11β-hydroxysteroid
dehydrogenases type 2 (HSD11B2)
Oncosterone (OCDO) is an enzymatic oxidation product of CT and is not an
autoxidation product of cholesterol (Poirot, Soules, Mallinger, Dalenc
& Silvente-Poirot, 2018). Oncosterone was shown to be generated from CT
by the 3β-hydroxysteroid dehydrogenase type 2 (HSD11B2) (Voisin et al.,
2017). HSD11B2 is expressed in BC from patients and BC cell lines, while
weakly or not expressed in normal breast tissue, and the expression of
HSD11B2 paralleled OCDO levels, establishing that oncosterone is an
oncometabolite (Voisin et al., 2017). HSD11B2’s primary function is the
inactivation of cortisol by oxidation to produce cortisone (Chapman,
Holmes & Seckl, 2013). This reaction is known to be reverted by
HSD11B1, and HSD11B1 was earlier reported to reduce 7-ketocholesterol
into 7β-hydroxycholesterol (Mitic et al., 2013). HSD11B1 was also found
to catalyse the conversion of OCDO into CT (Voisin et al., 2017).
HSD11B1 requires hexose-6-phosphate dehydrogenase (H6PD) for the
regeneration of its cofactor NADPH in order to achieve a reductase
activity. In the absence of H6PD, it was reported that HSD11B1 functions
as an oxidase like HSD11B2 (Odermatt & Klusonova, 2015). HSD11B1 and
H6PD were found weakly or not expressed in the breast and in BC as well
as in BC cell lines showing that the eventual equilibrium of CT
oncosterone conversion was completely displaced in favour of oncosterone
production in BC (Voisin et al., 2017) .
The knock down of HSD11B2 in the ER(+)-BC cell line MCF-7 blocks the
endogenous production of oncosterone, cell proliferation and
clonogenicity in vitro and tumour growth in vivo . Addition
of exogenous oncosterone reverts the effect of HSD11B2 knock down
(Voisin et al., 2017). These data suggest that the oncosterone
biosynthesis enzyme HSD11B2 may constitute a target for the development
of inhibitors in BC treatment. Natural and synthetic inhibitors of
HSD11B2 have been described and it would be of interest to define their
impact on OCDO biosynthesis (Latif, Pardo, Hardy & Morris, 2005;
Morris, Latif, Hardy & Brem, 2007; Vitku et al., 2016; Zhou, Ye, Wu, Ye
& Chen, 2017). An open question and an exciting challenge will be to
develop HSD11B2 inhibitors that block oncosterone biosynthesis with
little or no impact on the cortisol metabolism to limit side effects
such as hypertension. Such inhibitors could display anticancer
properties in all BC-subtypes, offering new targeted therapies for TN
BC. Such a hypothesis should deserve further exploration.
Analysis of HSD11B2 expression in patient BC samples showed that it was
significantly higher than in normal matched tissue. Kaplan-Meier
analyses of several BC transcriptome patient datasets showed that high
levels of HSD11B2 mRNA were associated with a poor prognosis. High
expression levels of both ChEH subunits and HSD11B2 were associated with
the risk highest risk of patient mortality (Voisin et al., 2017). These
data strongly support the development of ChEH and HSD11B2 inhibitors for
BC treatment.