NON AMMALARSI DI CANCRO

Viene presentata, in questo articolo, un'ipotesi molto interessante che riguarda la possibilità di un metabolita del colesterolo, il 27-OHC sintetizzato in grande quantità nei macrofagi, di stimolare i recettori nucleari e di favorire la crescita tumorale, diminuendo la sensibilità dei recettori agli estrogeni (nei tumori estrogeno-dipendenti). Una prova ulteriore che la metabolomica è la disciplina del futuro e che la nutraceutica sarà una delle strade principali verso una reale prevenzione anche di malattie molto rilevanti, oltre che uno strumento sicuramente non accessorio di cura.

On Estrogen, Cholesterol Metabolism, and Breast Cancer

Margaret Warner, Ph.D., and Jan-Ake Gustafsson, M.D., Ph.D.

N Engl J Med 2014; 370:572-573February 6, 2014DOI: 10.1056/NEJMcibr1315176

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Article

Nuclear hormone receptors are highly specific to their hormone ligands. Androgens do not stimulate estrogen receptors, nor do progesterone, glucocorticoids, and mineralocorticoids. If this were not the case, the endocrine system would not function. If the hypothalamus did not specifically recognize estrogen, how would it signal to the pituitary during estrogen deficiency?

The presence of a second putative estrogen, 27-hydroxycholesterol (27-OHC), a cholesterol metabolite that is different in structure but similar in action to estradiol, could plausibly confer the same benefits and risks as estradiol. On the one hand, it might protect postmenopausal women from osteoporosis and the drying of skin and mucous membranes. On the other, it might increase the risk of breast cancer.

Does one role predominate? When the ovary ceases to produce estradiol, all the symptoms of menopause appear, regardless of the production of 27-OHC by macrophages. There is, however, epidemiologic evidence that lowering of cholesterol offers protection against breast cancer.1Perhaps, then, 27-OHC has more to do with the risk of breast cancer than protecting against symptoms associated with menopause. Perhaps this is why Nelson et al., in a recent study of 27-OHC, focused on breast-cancer models in mice.2

The investigators used several murine models of breast cancer involving alterations in cholesterol metabolism, lung metastasis, and dietary manipulations and, in so doing, showed that 27-OHC is an agonist of the estrogen receptor and increases the risk of breast cancer Figure 1FIGURE 1Pathways of Cholesterol Metabolism.. More specifically, they showed that in a breast-cancer cell line, 27-OHC stimulated only a fraction of genes (1500 of 8000) that are regulated by estradiol. In addition, 27-OHC stimulated the growth of the breast-cancer MCF-7 cell line by binding to and activating the estrogen receptor alpha, and (like estradiol) it was much less efficacious in increasing proliferation in tamoxifen-resistant cells. Also, by binding to and stimulating signaling by the liver X receptor (and not the estrogen receptor), 27-OHC stimulated lung metastasis in mice. And finally, the synthesis of 27-OHC was catalyzed by CYP27A1, an enzyme that is highly expressed in macrophages, including those infiltrating breast cancer.

Should CYP27A1 therefore be considered a target for the treatment of breast cancer? Before targeting of the synthesis of 27-OHC, an appreciation of its physiologic functions is warranted. Since macrophages synthesize a great deal of 27-OHC, its role as a signaling molecule should be investigated. One possibility is that 27-OHC is itself a hormone, synthesized in macrophages and signaling to the liver to prepare it for an incoming load of cholesterol. While acknowledging the large body of data generated by Nelson et al., we would suggest additional approaches to test the effect of 27-OHC on tumor growth, such as more detailed histochemical analyses of 27-OHC–stimulated tumors, which could differentiate between, for example, cystic growth and changes in vascularity.

The idea that intratumoral levels of a cholesterol metabolite could be high enough to stimulate nuclear receptors and influence tumor growth is interesting and also suggests that high levels of 27-OHC could down-regulate the estrogen receptors and lead to hormone insensitivity. The intratumoral milieu is an understudied aspect of tumor biology. The time is right to begin to study the metabolomics of tumor-biopsy specimens alongside standard immunohistochemical analysis.