Abstract
Epidemiological evidence suggests that carotenoids prevent several types of cancer, including mammary and endometrial cancers. On the other hand, such studies have also shown that estrogens are the most important risk factors for these cancer types. Genistein, the phytoestrogen mainly found in soy, also shows significant estrogenic activity when tested at concentrations found in human blood. The aim of this study was to determine whether carotenoids inhibit signaling of steroidal estrogen and phytoestrogen which could explain their cancer preventive activity. Similar to the known effect of 17β-estradiol (E2), treatment of breast (T47D and MCF-7) and endometrial (ECC-1) cancer cells with phytoestrogens induced cell proliferation, cell-cycle progression and transactivation of the estrogen response element (ERE). However, each of the tested carotenoids (lycopene, phytoene, phytofluene, and β-carotene) inhibited cancer cell proliferation induced by either E2 or genistein. The inhibition of cell growth by lycopene was accompanied by slow down of cell-cycle progression from G1 to S phase. Moreover, the carotenoids inhibited estrogen-induced transactivation of ERE that was mediated by both estrogen receptors (ERs) ERα and ERβ. The possibility that this inhibition results from competition of carotenoid-activated transcription systems on a limited pool of shared coactivators with the ERE transcription system was tested. Although cotransfection of breast and endometrial cancer cells with four different coactivators (SRC-1, SRC-2, SRC-3, and DRIP) strongly stimulated ERE reporter gene activity, it did not oppose the inhibitory effect of carotenoids. These results suggest that dietary carotenoids inhibit estrogen signaling of both 17β-estradiol and genistein, and attenuate their deleterious effect in hormone-dependent malignancies.
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References
Hulka BS, Moorman PG (2001) Breast cancer: hormones and other risk factors. Maturitas 38:103–113
Magee PJ, Rowland IR (2004) Phyto-oestrogens, their mechanism of action: current evidence for a role in breast and prostate cancer. Br J Nutr 91:513–531
Setchell KD (1998) Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones. Am J Clin Nutr 68:1333s–1346s
Maggiolini M, Bonofiglio D, Marsico S, Panno ML, Cenni B, Picard D, Ando S (2001) Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol Pharmacol 60:595–602
Hsieh CY, Santell RC, Haslam SZ, Helferich WG (1998) Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 58:3833–3838
Murata M, Midorikawa K, Koh M, Umezawa K, Kawanishi S (2004) Genistein and daidzein induce cell proliferation and their metabolites cause oxidative DNA damage in relation to isoflavone-induced cancer of estrogen-sensitive organs. Biochemistry 43:2569–2577
Matsumura A, Ghosh A, Pope GS, Darbre PD (2005) Comparative study of oestrogenic properties of eight phytoestrogens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol 94:431–443
Dees C, Foster JS, Ahamed S, Wimalasena J (1997) Dietary estrogens stimulate human breast cells to enter the cell cycle. Environ Health Perspect 3:633–636
Po LS, Chen ZY, Tsang DS, Leung LK (2002) Baicalein and genistein display differential actions on estrogen receptor (ER) transactivation and apoptosis in MCF-7 cells. Cancer Lett 187:33–40
Wang C, Kurzer MS (1998) Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer 31:90–100
Levenson AS, Gehm BD, Pearce ST, Horiguchi J, Simons LA, Ward JE III, Jameson JL, Jordan VC (2003) Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER alpha. Int J Cancer 104:587–596
Ito Y, Shimizu H, Yoshimura T, Ross RK, Kabuto M, Takatsuka N, Tokui N, Suzuki K, Shinohara R (1999) Serum concentrations of carotenoids, alpha-tocopherol, fatty acids, and lipid peroxides among Japanese in Japan, and Japanese and Caucasians in the US. Int J Vitam Nutr Res 69:385–395
Sharoni Y, Danilenko M, Dubi N, Ben-Dor A, Levy J (2004) Carotenoids and transcription. Arch Biochem Biophys 430:89–96
Gaudet MM, Britton JA, Kabat GC, Steck-Scott S, Eng SM, Teitelbaum SL, Terry MB, Neugut AI, Gammon MD (2004) Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev 13:1485–1494
Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ (2005) Plasma carotenoids, retinol, and tocopherols and risk of breast cancer. Am J Epidemiol 161:153–160
Jain MG, Rohan TE, Howe GR, Miller AB (2000) A cohort study of nutritional factors and endometrial cancer. Eur J Epidemiol 16:899–905
McCann SE, Freudenheim JL, Marshall JR, Brasure JR, Swanson MK, Graham S (2000) Diet in the epidemiology of endometrial cancer in western New York (United States). Cancer Causes Control 11:965–974
Amir H, Karas M, Giat J, Danilenko M, Levy R, Yermiahu T, Levy J, Sharoni Y (1999) Lycopene and 1,25-dihydroxyvitamin-D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 33:105–112
Levy J, Bosin E, Feldman B, Giat Y, Miinster A, Danilenko M, Sharoni Y (1995) Lycopene is a more potent inhibitor of human cancer cell proliferation than either a-carotene or b-carotene. Nutr Cancer 24:257–267
Prakash P, Russell RM, Krinsky NI (2001) In vitro inhibition of proliferation of estrogen-dependent and estrogen-independent human breast cancer cells treated with carotenoids or retinoids. J Nutr 131:1574–1580
Pastori M, Pfander H, Boscoboinik D, Azzi A (1998) Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun 250:582–585
Nahum A, Hirsch K, Danilenko M, Watts CK, Prall OW, Levy J, Sharoni Y (2001) Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E-cdk2 complexes. Oncogene 20:3428–3436
Karas M, Amir H, Fishman D, Danilenko M, Segal S, Nahum A, Koifmann A, Giat Y, Levy J, Sharoni Y (2000) Lycopene interferes with cell cycle progression and insulin-like growth factor I signaling in mammary cancer cells. Nutr Cancer 36:101–111
Tabibzadeh S, Kaffka KL, Kilian PL, Satyaswaroop PG (1990) Human endometrial epithelial cell lines for studying steroid and cytokine actions. In Vitro Cell Dev Biol 26:1173–1179
Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J, et al (1996) Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 88:1560–1570
Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK, Haapakoski J, Rautalahti M, Hartman AM, Palmgren J, et al (1995) Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 62:1427S–1430S
Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, et al (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. New Engl J Med 334:1150–1155
Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL (1995) Antiestrogen inhibition of cell cycle progression in breast cancer cells in associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol Endocrinol 9:1804–1813
Mak HY, Parker MG (2001) Use of suppressor mutants to probe the function of estrogen receptor-p160 coactivator interactions. Mol Cell Biol 21:4379–4390
Xu X, Wang HJ, Murphy PA, Cook L, Hendrich S (1994) Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women. J Nutr 124:825–832
Morton MS, Wilcox G, Wahlqvist ML, Griffiths K (1994) Determination of lignans and isoflavonoids in human female plasma following dietary supplementation. J Endocrinol 142:251–259
Ben-Dor A, Steiner M, Gheber L, Danilenko M, Dubi N, Linnewiel K, Zick A, Sharoni Y, Levy J (2005) Carotenoids activate the antioxidant response element transcription system. Mol Cancer Ther 4:177–186
Wang X, Kilgore MW (2002) Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol 194:123–133
Kietz S, Thomsen JS, Matthews J, Pettersson K, Strom A, Gustafsson JA (2004) The Ah receptor inhibits estrogen-induced estrogen receptor beta in breast cancer cells. Biochem Biophys Res Commun 320:76–82
Wormke M, Castro-Rivera E, Chen I, Safe S (2000) Estrogen and aryl hydrocarbon receptor expression and crosstalk in human Ishikawa endometrial cancer cells. J Steroid Biochem Mol Biol 72:197–207
Song MR, Lee SK, Seo YW, Choi HS, Lee JW, Lee MO (1998) Differential modulation of transcriptional activity of oestrogen receptors by direct protein–protein interactions with retinoid receptors. Biochem J 336:711–717
Nesaretnam K, Jin Lim E, Reimann K, Lai LC (2000) Effect of a carotene concentrate on the growth of human breast cancer cells and pS2 gene expression. Toxicology 151:117–126
Tibaduiza EC, Fleet JC, Russell RM, Krinsky NI (2002) Excentric cleavage products of beta-carotene inhibit estrogen receptor positive and negative breast tumor cell growth in vitro and inhibit activator protein-1-mediated transcriptional activation. J Nutr 132:1368–1375
Musgrove EA, Hamilton JA, Lee CS, Sweeney KJ, Watts CK, Sutherland RL (1993) Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol Cell Biol 13:3577–3587
Sutherland RL, Watts CK, Musgrove EA (1993) Cyclin gene expression and growth control in normal and neoplastic human breast epithelium. J Steroid Biochem Mol Biol 47:99–106
Watts CK, Sweeney KJ, Warlters A, Musgrove EA, Sutherland RL (1994) Antiestrogen regulation of cell cycle progression and cyclin D1 gene expression in MCF-7 human breast cancer cells. Breast Cancer Res Treat 31:95–105
Acknowledgments
We thank Dr. Zohar Nir, LycoRed Natural Products Industries, Beer Sheva, Israel, for donating purified lycopene, phytoene and phytofluene. We thank Dr. M. Parker (Imperial Cancer Research Fund, London, UK), Dr. P. Chambon (Institute of Genetic and Cellular and Molecular Biology, Strasburg, France), Dr. R.M. Evans (Salk Institute, La Jolla, CA, USA), and Dr. L.P. Freedman (Cornell University, NY, USA) for donating the plasmids that were used in this study. The studies were supported in part by the Israel Science Foundation founded by the Israel Academy of Science and Humanities; by LycoRed Natural Products Industries, Beer-Sheva, Israel; and by the S. Daniel Abraham International Center for Health and Nutrition, Ben-Gurion University of the Negev.
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Hirsch, K., Atzmon, A., Danilenko, M. et al. Lycopene and other carotenoids inhibit estrogenic activity of 17β-estradiol and genistein in cancer cells. Breast Cancer Res Treat 104, 221–230 (2007). https://doi.org/10.1007/s10549-006-9405-7
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DOI: https://doi.org/10.1007/s10549-006-9405-7