Glyceollins trigger anti-proliferative effects through estradiol-dependent and independent pathways in breast cancer cells

Cell Communication and Signaling

Research

Marie Lelong¹  Frederic Percevault¹  Farzad Pakdel¹  François Ferriere¹  Sylvain Lecomte¹  Christian Saligaut¹  Frederic Chalmel²  Claire Surel³  Theo Efstathiou³  Nicolas Plu³ 

[1] Institut de Recherche en Santé-Environnement-Travail (IRSET), University of Rennes 1, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France;Inserm U1085, Team Transcription, Environment and Cancer, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France;Institut de Recherche en Santé-Environnement-Travail (IRSET), University of Rennes 1, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France;Inserm U1085, Team Viral and Chemical Environment & Reproduction, 9 Avenue du Pr Léon Bernard, 35000, Rennes, France;Laboratoire Nutrinov, Technopole Atalante Champeaux, 8 rue Jules Maillard de la Gournerie, 35012, Rennes Cedex, France;

关键词: Glyceollins;    Estrogen receptors;    Cell proliferation;    Transcriptomic;    Gene expression;    Breast cancer;   

DOI  :  10.1186/s12964-017-0182-1

 received in 2017-03-10, accepted in 2017-06-20,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundEstrogen receptors (ER) α and β are found in both women and men in many tissues, where they have different functions, including having roles in cell proliferation and differentiation of the reproductive tract. In addition to estradiol (E2), a natural hormone, numerous compounds are able to bind ERs and modulate their activities. Among these compounds, phytoestrogens such as isoflavones, which are found in plants, are promising therapeutics for several pathologies. Glyceollins are second metabolites of isoflavones that are mainly produced in soybean in response to an elicitor. They have potentially therapeutic actions in breast cancer by reducing the proliferation of cancer cells. However, the molecular mechanisms driving these effects remain elusive.MethodsFirst, to determine the proliferative or anti-proliferative effects of glyceollins, in vivo and in vitro approaches were used. The length of epithelial duct in mammary gland as well as uterotrophy after treatment by E2 and glyceollins and their effect on proliferation of different breast cell line were assessed. Secondly, the ability of glyceollin to activate ER was assessed by luciferase assay. Finally, to unravel molecular mechanisms involved by glyceollins, transcriptomic analysis was performed on MCF-7 breast cancer cells.ResultsIn this study, we show that synthetic versions of glyceollin I and II exert anti-proliferative effects in vivo in mouse mammary glands and in vitro in different ER-positive and ER-negative breast cell lines. Using transcriptomic analysis, we produce for the first time an integrated view of gene regulation in response to glyceollins and reveal that these phytochemicals act through at least two major pathways. One pathway involving FOXM1 and ERα is directly linked to proliferation. The other involves the HIF family and reveals that stress is a potential factor in the anti-proliferative effects of glyceollins due to its role in increasing the expression of REDD1, an mTORC1 inhibitor.ConclusionOverall, our study clearly shows that glyceollins exert anti-proliferative effects by reducing the expression of genes encoding cell cycle and mitosis-associated factors and biomarkers overexpressed in cancers and by increasing the expression of growth arrest-related genes. These results reinforce the therapeutic potential of glyceollins for breast cancer.

【 授权许可】

CC BY   
© The Author(s). 2017