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Cholesterol metabolites can promote or suppress breast cancer.


Should we inhibit the production of cholesterol in order to treat or prevent breast cancer ?
The question is not simple because conflicting epidemiological data were obtained on the use of statins (inhibitors of cholesterol biosynthesis), which was associated with either zero, decreased or increased breast cancer risk. In addition, a recent epidemiological study showed that the use of statins for periods of more than 10 years would double the risk of invasive breast cancer in postmenopausal patients (1). A disconcerting result that raises questions.

The team of Marc Poirot and Sandrine Silvente-Poirot (co-founders of Affichem) just published a perspective in the prestigious journal "Science" (2) in which they discuss this issue in relation to their work on Dendrogenin A and recent results obtained by different U.S. research laboratories. Indeed, researches from different laboratories show that the influence of cholesterol metabolism in the progression or suppression of breast cancers could explain these contradictory studies.

Cholesterol has been shown to promote the progression and aggressiveness of breast tumors in different models of animal studies, suggesting that cholesterol or its metabolites are involved in the development of breast cancer. Recent studies confirm these results and show that a cholesterol derivative, 27-hydroxycholesterol (27HC), stimulates tumor growth by interacting with the estrogen receptor in several models of breast cancer. These observations seem to be of clinical relevance since an increased expression of the enzyme eliminating 27HC was associated with increased survival of patients with breast cancer. Moreover, higher rate of 27HC were detected in breast tumors compared to non-tumor tissue, showing an increase of the production of 27HC during mammary carcinogenesis (3,4).

Conversely, Dendrogenin A, a natural metabolite of cholesterol discovered by Dr Marc Poirot and Dr Sandrine Silvente-Poirot, inhibits the growth of breast cancers. It stimulates the re-differentiation of tumors (return to a normal state) and increases animal survival. Interestingly, the level of Dendrogenin A is decreased in breast cancers in patients compared with normal tissue, indicating a deregulation of the production of Dendrogenin A during carcinogenesis. The biological properties of Dendrogenin A and its reduced level in tumors suggest a physiological function in the maintenance of the integrity and the differentiation of cells (4).

Therefore, it appears that some derivatives of cholesterol stimulate the progression of breast cancers while others suppress them. A metabolic balance between the production of tumor promoters and tumor suppressors would regulate the development of breast cancers. An important perspective that Dr Marc Poirot and Dr Sandrine Silvente-Poirot study, and that should lead to the development of new therapeutic approaches for breast cancer but also for other cancers.

Manuscript Title: "Cholesterol and Cancer, In the Balance"
Manuscript Number: 1252787
Issue Date: 03/28/2014
Volume: 343 - Page: 1445
http://www.sciencemag.org/cgi/content/short/343/6178/1445


Marc Poirot, Sandrine Silvente-Poirot
Équipe “métabolisme des stérols et innovations thérapeutiques en oncologie", Inserm UMR 1037-Université Toulouse III, Centre de Recherche en Cancérologie de Toulouse, Institut Claudius Regaud, Toulouse
marc.poirot@inserm.fr
sandrine.poirot@inserm.fr


(1). Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age. McDougall JA et al, Cancer Epidemiol. Biomarkers Prev. 22,1529 (2013)
(2). Cholesterol and Cancer, In the balance. Silvente-Poirot S and Poirot M, Science 343, 1445 (2014)
(3). 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Nelson E.R et al, Science 342, 1094 (2013)
(4). 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Wu Q et al, Cell Rep. 5, 637 (2013)
(5). Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. de Medina P et al, Nat. commun. 4, 1840 (2013)

 
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