Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor

Abstract

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer

“…Patient breast cancer samples showed significant increase in OCDO levels and greater ChEH and 11bHSD2 protein expression compared with normal tissues (15). The analysis of several human breast cancer mRNA databases indicated that 11bHSD2 and ChEH subunit overexpression was correlated with a higher risk of patient death in breast cancer and that high GR expression or activation was correlated with poor therapeutic response or prognosis in many solid tumors including breast cancer (15). Interestingly, ChEH inhibition and 11bHSD2 silencing inhibited OCDO production and tumor growth and mifepristone, a GR antagonist, as well as GR silencing inhibits OCDO-induced tumor cell proliferation (15).…”

“…Interestingly, an oncometabolism downstream of 5,6a-EC and 5,6b-EC (5,6EC) was identified in breast cancer in human and animal models (15). The cholesterol epoxide hydrolase (ChEH), formed by the D8D7I and 3b-hydroxysterol-D 7 -reductase (DHCR7) enzymes, is known to metabolize 5,6-ECs into cholestane-3b,5a,6b-triol (CT) in normal tissues (4,16).…”

“…Moreover, the effect of OCDO on inflammation through GR and/or LXRs needs to be explored because chronic low-grade inflammation is a hallmark of obesity, and has been proposed as a mechanistic link between obesity and cancer. Patient breast cancer samples showed significant increase in OCDO levels and greater ChEH and 11bHSD2 protein expression compared with normal tissues (15). The analysis of several human breast cancer mRNA databases indicated that 11bHSD2 and ChEH subunit overexpression was correlated with a higher risk of patient death in breast cancer and that high GR expression or activation was correlated with poor therapeutic response or prognosis in many solid tumors including breast cancer (15).…”

“…The analysis of several human breast cancer mRNA databases indicated that 11bHSD2 and ChEH subunit overexpression was correlated with a higher risk of patient death in breast cancer and that high GR expression or activation was correlated with poor therapeutic response or prognosis in many solid tumors including breast cancer (15). Interestingly, ChEH inhibition and 11bHSD2 silencing inhibited OCDO production and tumor growth and mifepristone, a GR antagonist, as well as GR silencing inhibits OCDO-induced tumor cell proliferation (15). Thus, targeting this oncometabolism and GR represents new opportunities for therapeutic interventions in breast cancer and potentially other cancers presenting such deregulations.…”

Development of a novel HPTLC-based method for the simultaneous quantification of clinically relevant lipids from cells and tissue extracts

“…In cancer, they have been demonstrated to play an important role in the regulation of cancer progression. Their functions include the regulation of cellular signaling pathways involved in cell cycle regulation as well as other pathways regulating cancer cell migration and survival [5][6][7]. In several types of cancer, plasma cholesterol levels have been shown to regulate tumor formation and cancer aggressiveness [8,9].…”