Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model

• Published in: Toxicology and applied pharmacology 2013-06, Vol.269 (2), p.132-140
• Main Authors: van Duursen, Majorie B.M., Smeets, Evelien E.J.W., Rijk, Jeroen C.W., Nijmeijer, Sandra M., van den Berg, Martin
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; aromatase; bioavailability; Biological and medical sciences; Breast cancer model; Breast Neoplasms - drug therapy; Cell Line, Tumor; CELL PROLIFERATION; Cell Proliferation - drug effects; Dietary Supplements; Dose-Response Relationship, Drug; Drug Antagonism; ESTROGENS; expression patterns; Female; Gene Expression Regulation, Neoplastic - drug effects; gene-expression; Gynecology. Andrology. Obstetrics; H295R; Humans; IN VITRO; Letrozole; Mammary gland diseases; MAMMARY GLANDS; mcf-7 cells; Medical sciences; Menopausal supplements; Menopause; metabolism; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NEOPLASMS; Phytoestrogens - pharmacology; plasma estrogen; RECEPTORS; Receptors, Estrogen - physiology; Steroidogenesis; TAMOXIFEN; Toxicology; TUMOR CELLS; Tumors; WOMEN
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.03.014

Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided. •Supplements containing phytoestrogens are commonly used by women with breast cancer.•Phytoestrogens alter steroidogenesis in a co-culture breast cancer model.•Letrozole or tamoxifen treatment is used to inhibit ER-dependent breast tumor growth.•Phytoestrogens induce in vitro tumor cell growth, even in combination with LET or TAM.•Use of phytoestrogens during breast cancer treatment should better be avoided.