Genistein: Its Role in Breast Cancer Growth and Metastasis

Author(s): Vidya Mukund*

Journal Name: Current Drug Metabolism

Volume 21 , Issue 1 , 2020

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Graphical Abstract:


Background: Genistein being a phytoestrogen imitates the characteristics of estrogen, which can be useful to treat conditions by reducing the estrogen levels at the time of menopause, osteoporosis and high risk for breast cancer.

Objective: The superior binding of genistein to ERβ might help in reducing breast malignancy risk.

Conclusion: Genistein induces cell cycle arrest, anti-metastatic properties and ultimately affects the breast cancer cell growth by multiple mechanisms. Genistein-mediated anti-proliferative or anti-growth effects are usually observed at higher concentrations. These signaling pathways involve the decrease of NF-κB, HIF-1α, VEGF, and an increase of tumor suppressor p21. This will provide further insight into understanding the biology of transcription factors NF-κB, and HIF-1α in breast cancer.

Keywords: Breast cancer, genistein, cell proliferation, metastasis, signaling molecules, phytoestrogen.

Khan, S.A.; Chatterton, R.T.; Michel, N.; Bryk, M.; Lee, O.; Ivancic, D.; Heinz, R.; Zalles, C.M.; Helenowski, I.B.; Jovanovic, B.D.; Franke, A.A.; Bosland, M.C.; Wang, J.; Hansen, N.M.; Bethke, K.P.; Dew, A.; Coomes, M.; Bergan, R.C. Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial. Cancer Prev. Res. (Phila.), 2012, 5(2), 309-319.
[] [PMID: 22307566]
Kwon, Y. Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies. Food Sci. Nutr., 2014, 2(6), 613-622.
[] [PMID: 25493176]
Onitilo, A.A.; Engel, J.M.; Greenlee, R.T.; Mukesh, B.N. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin. Med. Res., 2009, 7(1-2), 4-13.
Lakhani, S.R.; Van De Vijver, M.J.; Jacquemier, J.; Anderson, T.J.; Osin, P.P.; McGuffog, L.; Easton, D.F. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J. Clin. Oncol., 2002, 20(9), 2310-2318.
[] [PMID: 11981002]
Fan, S.; Meng, Q.; Auborn, K.; Carter, T.; Rosen, E.M. BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br. J. Cancer, 2006, 94(3), 407-426.
[] [PMID: 16434996]
Tong, C.W.S.; Wu, M.; Cho, W.C.S.; To, K.K.W. Recent advances in the treatment of breast cancer. Front. Oncol., 2018, 8, 227.
[] [PMID: 29963498]
Shah, R.; Rosso, K.; Nathanson, S.D. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World J. Clin. Oncol., 2014, 5(3), 283-298.
[] [PMID: 25114845]
Zeng, L.; Yan, J.; Luo, L.; Ma, M.; Zhu, H. Preparation and characterization of (-)-Epigallocatechin-3-gallate (EGCG)-loaded nanoparticles and their inhibitory effects on Human breast cancer MCF-7 cells. Sci. Rep., 2017, 7, 45521.
[] [PMID: 28349962]
Ziaei, S.; Halaby, R. Dietary isoflavones and breast cancer risk. Medicines (Basel), 2017, 4(2), 18.
[] [PMID: 28930233]
Walter, E. Genistin (an isoflavone glucoside) and its aglucone, genistein, from soybeans. J. Am. Chem. Soc., 1941, 63, 3273-3276.
Nadal-Serrano, M.; Pons, D.G.; Sastre-Serra, J.; Blanquer-Rosselló, Mdel.M.; Roca, P.; Oliver, J. Genistein modulates oxidative stress in breast cancer cell lines according to ERα/ERβ ratio: effects on mitochondrial functionality, sirtuins, uncoupling protein 2 and antioxidant enzymes. Int. J. Biochem. Cell Biol., 2013, 45(9), 2045-2051.
[] [PMID: 23871935]
Tůmová, L.; Tůma, J. The effect of UV light on isoflavonoid production in Genista tinctoria culture in vitro. Acta Physiol. Plant., 2011, 33, 635-640.
Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology, 1998, 139(10), 4252-4263.
[] [PMID: 9751507]
Szkudelska, K.; Nogowski, L. Genistein--a dietary compound inducing hormonal and metabolic changes. J. Steroid Biochem. Mol. Biol., 2007, 105(1-5), 37-45.
[] [PMID: 17588743]
McCarty, M.F. Isoflavones Made Simple-Agonist Activity for the Beta- Type Estrogen Receptor May Mediate Their Health Benefits. In: Complementary and Alternative Therapies and the Aging Population; Watson, R.R., Ed.; Elsevier: Amsterdam, 2009, pp. 475-522.
Le Bail, J.C.; Varnat, F.; Nicolas, J.C.; Habrioux, G. Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Lett., 1998, 130(1-2), 209-216.
[] [PMID: 9751276]
Polkowski, K.; Mazurek, A.P. Biological properties of genistein. A review of in vitro and in vivo data. Acta Pol. Pharm., 2000, 57, 135-155.
Nagaraju, G.P.; Zafar, S.F.; El-Rayes, B.F. Pleiotropic effects of genistein in metabolic, inflammatory, and malignant diseases. Nutr. Rev., 2013, 71(8), 562-572.
[] [PMID: 23865800]
Ramos, S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J. Nutr. Biochem., 2007, 18(7), 427-442.
[] [PMID: 17321735]
Zhou, J-R.; Gugger, E.T.; Tanaka, T.; Guo, Y.; Blackburn, G.L.; Clinton, S.K. Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J. Nutr., 1999, 129(9), 1628-1635.
[] [PMID: 10460196]
Li, D.; Yee, J.A.; McGuire, M.H.; Murphy, P.A.; Yan, L. Soybean isoflavones reduce experimental metastasis in mice. J. Nutr., 1999, 129(5), 1075-1078.
[] [PMID: 10222402]
Maggiolini, M.; Vivacqua, A.; Fasanella, G.; Recchia, A.G.; Sisci, D.; Pezzi, V.; Montanaro, D.; Musti, A.M.; Picard, D.; Andò, S. The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17β-estradiol and phytoestrogens in breast cancer cells. J. Biol. Chem., 2004, 279(26), 27008-27016.
[] [PMID: 15090535]
Weinberg, R.A. The biology of cancer; Garland Science: New York, 2007.
Pavese, J.M.; Farmer, R.L.; Bergan, R.C. Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev., 2010, 29(3), 465-482.
[] [PMID: 20730632]
Seo, H.S.; Choi, H.S.; Choi, H.S.; Choi, Y.K.; Um, J-Y.; Choi, I.; Shin, Y.C.; Ko, S-G. Phytoestrogens induce apoptosis via extrinsic pathway, inhibiting nuclear factor-kappaB signaling in HER2-overexpressing breast cancer cells. Anticancer Res., 2011, 31(10), 3301-3313.
[PMID: 21965740]
Pan, H.; Zhou, W.; He, W.; Liu, X.; Ding, Q.; Ling, L.; Zha, X.; Wang, S. Genistein inhibits MDA-MB-231 triple-negative breast cancer cell growth by inhibiting NF-κB activity via the Notch-1 pathway. Int. J. Mol. Med., 2012, 30(2), 337-343.
[] [PMID: 22580499]
Anastasius, N.; Boston, S.; Lacey, M.; Storing, N.; Whitehead, S.A. Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway. J. Steroid Biochem. Mol. Biol., 2009, 116(1-2), 50-55.
[] [PMID: 19406242]
Shao, Z-M.; Wu, J.; Shen, Z-Z.; Barsky, S.H. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res., 1998, 58(21), 4851-4857.
[PMID: 9809990]
de la Parra, C.; Castillo-Pichardo, L.; Cruz-Collazo, A.; Cubano, L.; Redis, R.; Calin, G.A.; Dharmawardhane, S. Soy isoflavone genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein. Nutr. Cancer, 2016, 68(1), 154-164.
[] [PMID: 26771440]
Barnes, S. The chemopreventive properties of soy isoflavonoids in animal models of breast cancer. Breast Cancer Res. Treat., 1997, 46(2-3), 169-179.
[] [PMID: 9478272]
Allred, C.D.; Ju, Y.H.; Allred, K.F.; Chang, J.; Helferich, W.G. Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. Carcinogenesis, 2001, 22(10), 1667-1673.
[] [PMID: 11577007]
Varinska, L.; Gal, P.; Mojzisova, G.; Mirossay, L.; Mojzis, J. Soy and breast cancer: focus on angiogenesis. Int. J. Mol. Sci., 2015, 16(5), 11728-11749.
[] [PMID: 26006245]
Hsieh, C-Y.; Santell, R.C.; Haslam, S.Z.; Helferich, W.G. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res., 1998, 58(17), 3833-3838.
[PMID: 9731492]
Adams, J.M.; Cory, S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene, 2007, 26(9), 1324-1337.
[] [PMID: 17322918]
Bhadada, S.V.; Goyal, B.R.; Patel, M.M. Angiogenic targets for potential disorders. Fundam. Clin. Pharmacol., 2011, 25(1), 29-47.
[] [PMID: 20199582]
Yaghjyan, L.; Colditz, G.A. Estrogens in the breast tissue: a systematic review. Cancer Causes Control, 2011, 22(4), 529-540.
[] [PMID: 21286801]
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med., 1971, 285(21), 1182-1186.
[] [PMID: 4938153]
Ferrara, N. VEGF as a therapeutic target in cancer. Oncology, 2005, 69(Suppl. 3), 11-16.
[] [PMID: 16301831]
Claesson-Welsh, L.; Welsh, M. VEGFA and tumour angiogenesis. J. Intern. Med., 2013, 273(2), 114-127.
[] [PMID: 23216836]
Miller, K.; Wang, M.; Gralow, J.; Dickler, M.; Cobleigh, M.; Perez, E.A.; Shenkier, T.; Cella, D.; Davidson, N.E. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med., 2007, 357(26), 2666-2676.
[] [PMID: 18160686]
Fotsis, T.; Pepper, M.; Adlercreutz, H.; Fleischmann, G.; Hase, T.; Montesano, R.; Schweigerer, L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc. Natl. Acad. Sci. USA, 1993, 90(7), 2690-2694.
[] [PMID: 7681986]
Hoff, P.M.; Machado, K.K. Role of angiogenesis in the pathogenesis of cancer. Cancer Treat. Rev., 2012, 38(7), 825-833.
[] [PMID: 22677191]
Berman, A.T.; Thukral, A.D.; Hwang, W-T.; Solin, L.J.; Vapiwala, N. Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment. Clin. Breast Cancer, 2013, 13(2), 88-94.
[] [PMID: 23218473]
Nishida, N.; Yano, H.; Nishida, T.; Kamura, T.; Kojiro, M. Angiogenesis in cancer. Vasc. Health Risk Manag., 2006, 2(3), 213-219.
[] [PMID: 17326328]
Guo, Y.; Wang, S.; Hoot, D.R.; Clinton, S.K. Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones. J. Nutr. Biochem., 2007, 18(6), 408-417.
[] [PMID: 17142033]
Buteau-Lozano, H.; Velasco, G.; Cristofari, M.; Balaguer, P.; Perrot-Applanat, M. Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. J. Endocrinol., 2008, 196(2), 399-412.
[] [PMID: 18252963]
Yu, X.; Mi, M.; Zhu, J. Genistein inhibits the expression of vascular endothelial growth factor in MDA-MB-453 breast cancer cells. U.S. Chin. J. Lymphol. Oncol., 2008, 7, 8-13.
Piao, M.; Mori, D.; Satoh, T.; Sugita, Y.; Tokunaga, O. Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the down-regulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis. Endothelium, 2006, 13(4), 249-266.
[] [PMID: 16990182]
Mahmoud, A.M.; Yang, W.; Bosland, M.C. Soy isoflavones and prostate cancer: a review of molecular mechanisms. J. Steroid Biochem. Mol. Biol., 2014, 140, 116-132.
[] [PMID: 24373791]
Bergan, R.; Kyle, E.; Nguyen, P.; Trepel, J.; Ingui, C.; Neckers, L. Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin. Clin. Exp. Metastasis, 1996, 14(4), 389-398.
[] [PMID: 8878413]
Sawai, H.; Okada, Y.; Funahashi, H.; Matsuo, Y.; Takahashi, H.; Takeyama, H.; Manabe, T. Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation. Mol. Cancer, 2005, 4, 37.
[] [PMID: 16209712]
Sieg, D.J.; Hauck, C.R.; Ilic, D.; Klingbeil, C.K.; Schaefer, E.; Damsky, C.H.; Schlaepfer, D.D. FAK integrates growth-factor and integrin signals to promote cell migration. Nat. Cell Biol., 2000, 2(5), 249-256.
[] [PMID: 10806474]
El Touny, L.H.; Banerjee, P.P. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res., 2009, 69(8), 3695-3703.
[] [PMID: 19351854]

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Article Details

Year: 2020
Published on: 13 May, 2020
Page: [6 - 10]
Pages: 5
DOI: 10.2174/1389200221666200120121919
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