PLoS One. 2013 Apr 4;8(4):e60567. doi: 10.1371/journal.pone.0060567.

Estrogenic potency of benzophenone UV filters in breast cancer cells: proliferative and transcriptional activity substantiated by docking analysis.

Kerdivel G, Le Guevel R, Habauzit D, Brion F, Ait-Aissa S, Pakdel F.

Transcription, Environment and Cancer Group, Institut de Recherche sur la Santé, Environnement et Travail (IRSET), INSERM U1085, Université de Rennes 1, Rennes, France.

 

Abstract

The results from recent studies show that some benzophenones (BPs) and their hydroxylated metabolites can function as weak estrogens (E2) in the environment. However, little is known about the structure-activity relationship of these molecules. We have examined the effects of exposure to ten different BPs on the proliferation of estrogen receptor (ER)-positive breast cancer cells and on the transcriptional activity of E2-target genes. We analyzed two genes that are tightly linked with estrogen-mediated proliferation, the CXCL12 and amphiregulin genes and two classical estrogen-responsive genes, the pS2 and progesterone receptor. Significant differences in the BPs efficiency to induce cell proliferation and endogenous E2-target gene expressions were observed. Using ERE-, Sp1-, AP1- and C3-reporter genes that contain different ER-binding sites in their promoter, we also showed significant differences in the BPs efficiency in activation of the ER transactivation. Together, our analyzes showed that the most active molecule is 4-hydroxy-BP. Docking analysis of the interaction of BPs in the ligand-binding pocket of ERα suggests that the minimum structural requirement for the estrogenic activity of BPs is a hydroxyl (OH) group in the phenyl A-ring that allows interaction with Glu-353, Arg-394 or Phe-404, which enhances the stability between BPs and ERα. Our modeling also indicates a loss of interaction between the OH groups of the phenyl B-ring and His-524. In addition, the presence of some OH groups in the phenyl B-ring can create repulsion forces, which may constrain helix 12 in an unfavorable position, explaining the differential estrogenic effects of BPs. These results, together with our analysis of BPs for their potency in activation of cell proliferation and ER-mediated transcription, report an improved understanding of the mechanism and structure-activity relationship of BPs.

PMID: 23593250

 

Supplement:

The increasing of breast cancer incidence during the last decades could not be only explained by the aging population and advances in diagnostics and mammography screening. Environmental factors may also play an important role in the development of breast cancer. Among these environmental factors, endocrine disrupting chemicals, such as xenoestrogens are suspected, as estrogens play important role in pathogenesis of breast cancer. Xenoestrogens are present in a number of substrates such as pesticides, chemical industry, food, water and cosmetic products. Thus, human population may be exposed to more than hundred xenoestrogens that could contribute to breast cancer development.

Benzophenones (BPs) UV filters used in cosmetics may be a significant source of xenoestrogens. In this study, we have analyzed the disturbance of estrogen receptor (ER) activity by several BPs in ER-positive human breast cancer cells. Based on differences in the residues that interact with the ER ligand-binding-site, BPs could lead to slight ligand-dependent conformational changes of activated ER. This could consequently alter ER-DNA interaction, ER-dependent transcription regulation and cellular responses. In regards to the proliferative effects of BPs, it seems plausible to postulate a potential pro-carcinogenic effect of these molecules in ER-positive tissues.

Moreover, because of their highly lipophilic characteristics, the UV filters are absorbed by the skin and rapidly enter the human body. Considering our results, direct application of BP-based sunscreen on the breast and the subsequent skin absorption could favor the proliferation of ERα-positive epithelial cells, increasing the probability of developing a breast cancer or stimulating the growth and progression of a pre-existing tumor.

Farzad PAKDEL-FIG1Figure 1. Schematic representation of the estrogenic activities of benzophenone UV filters.
Estrogen (E2) and benzophenones (BP) can both interact with the ligand-binding-domain of estrogen receptor (ER). Nevertheless, the nature of ER residues implicated in this interaction is different and could result in different conformational changes in the liganded ER. These differences could explain the variability in the transcriptional response to BPs observed on various E2-targets and the resulting phenotypical changes. Thus, although BPs are able to induce the proliferation of ER-positive breast cancer cells they are not able to mediate all signaling pathways governed by E2. This may be explained by the fact that ER-BP complexes may adopt a differential conformation than that induced by E2.

 

Acknowledgements: This work was supported by the Brittany Region, the French ministry of Ecology, Energy and Sustainable Development (PNRPE), the Post-Grenelle grant, the French League against Cancer (La Ligue Contre le Cancer), INSERM and CNRS.

Contact:

F. PAKDEL (Ph D)

IRSET, Inserm U1085, TREC team,

Université of Rennes 1, 35000 Rennes, France

Phone: (33) 2 23 23 51 32

Fax : (33) 2 23 23 67 94

E- mail : Farzad.Pakdel@univ-rennes1.fr

Website: www.irset.org

Trec team: http://www.irset.org/?page_id=356

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