Estrogens and Breast Cancer: Aromatase Activity Disruption (pp. 101-127)
Authors: Safa Moslemi and Gilles-Eric Seralini (Laboratory of Biochemistry and Molecular Biology, University of Caen)
Abstract: Breast is a hormone-dependent gland and estrogens play an important role in breast cancer promotion and growth in some instances, before a possible hormone-insensitivity. The irreversible conversion of androgens into estrogens is controlled by an enzymatic complexe called aromatase, composed of the ubiquitous reductase and a specific cytochrome P450 (CYP19). Thus, numerous pharmological treatments of breast cancers include not only the disruption of estrogen action through receptor partial blockade, but also aromatase inhibition. Xenobiotics or phytoestrogens may interfere with these treatments or promote endocrine disruption by themselves; their actions will be described at this level. There are several strategies to develop selective aromatase inhibitors such as screening of new compounds and molecular modeling to mimic the substrate shape or the active site by comparisons in different species. For instance, we have developed in the laboratory antisense stable phosphorothioate oligodeoxynucleotides directed against aromatase mRNA tertiary structures that are efficient in human cells. Moreover, the knowledge of equine aromatase allowed to test by site-directed mutagenesis and molecular modeling predictive hypotheses in the active site, that became fruitful in the design of new inhibitors, but also to understand the functioning of an essential member of the cytochrome P450 family. Besides known steroidal and non-steroidal inhibitors used in clinic, compounds found in our daily environment such as pollutants or dietary phytoestrogens are also described to interfere with aromatase and disturb the androgens/estrogens balance in normal individuals. Hormone-like compounds could contribute to the development or the prevention of breast cancer. There are several good evidences showing for instance that pesticides or industrial products may interfere with aromatase and/or estrogen metabolism resulting in more estrogenic and/or more carcinogenic environment for the cells via formation for instance of catecholestrogens and quinones. This could result in more estrogenic metabolites such as 16a-hydroxyestrone (16-OHE1) having high affinity for estrogen receptors and forming adducts. Furthermore, from epidemiological and in vitro studies, some pollutants showed to increase the 16-OHE1/2-OHE1ratio and this was associated with an increased risk of breast cancer. In the other hand, some isoflavonoids like equol were demonstrated in vitro to have anti-carcinogenic features at least in part as light estrogens. This may contribute to explain lower cancer rates in some populations consuming primarily plant-based diets. Therefore, xenobiotics depollution and consumption of flavonoid-rich plant foods could constitute two strategies for the prevention of some breast cancers.