5,6-Epoxy-cholesterols contribute to the anticancer pharmacology of Tamoxifen in breast cancer cells

Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study

“…It is interesting to note that the LXR is the master receptor of OS and is an indirect target of Tam [8,9]. Indeed, the LXR is involved in mediating the effects of Tam on breast tumor cell differentiation and death through the accumulation of 5,6α-EC and its sulfation product [8,9,17,18]. Altogether, these data demonstrate the potential importance of cholesterol and OS metabolism not only in BC progression but also in the pharmacological/therapeutic effects of Tam.…”

“…25-HC also elicits estrogenic effects in BC cells by activating ERα-mediated signaling [23] and as an LXR ligand it inhibits dendritic cell activation, leading to tumor immune escape and promotion [24]. It is interesting to note that the LXR is the master receptor of OS and is an indirect target of Tam [8,9]. Indeed, the LXR is involved in mediating the effects of Tam on breast tumor cell differentiation and death through the accumulation of 5,6α-EC and its sulfation product [8,9,17,18].…”

“…5,6-ECs were found to be the signaling compounds responsible of the induction by Tam of cancer cell differentiation and death [8,18,19]. 5,6-ECs are prone to extensive metabolism but enzymes discriminate both diastereoisomers (5,6-EC and 5,6β-EC) [4,7,8,18,20]. Moreover, additional OS such as 27-hydroxycholesterol (27-HC) or 25-hydroxycholesterol (25-HC) could also be candidate biomarkers.…”

“…5,6-EC are not normally present in cancer cells, but Tam (and analogues) was shown to induce in vitro 5,6-EC and 5,6-EC accumulation through a dual mechanism: 1) Tam stimulates cholesterol epoxidation through the activation of lipoperoxidation [18], and 2) inhibits ChEH in BC cells at pharmacologically active concentrations (IC50≈50nM) [8]. 5,6-ECs were found to be the signaling compounds responsible of the induction by Tam of cancer cell differentiation and death [8,18,19]. 5,6-ECs are prone to extensive metabolism but enzymes discriminate both diastereoisomers (5,6-EC and 5,6β-EC) [4,7,8,18,20].…”

“…AI are drugs commonly used to treat BC that work through a different mechanism to that of Tam, by inhibiting the production of estrogen from androgen [2]. Recent literature has highlighted the role of OS, oxygenated cholesterol derivatives, in BC progression [3][4][5][6] and resistance to Tam [7][8][9][10][11][12]. The impact of AI on OS metabolism is currently unknown.…”