Users Online: 526
Home Print this page Email this page
Home About us Editorial board Search Browse articles Submit article Ahead of Print Instructions Subscribe Contacts Login 


 
Previous article Browse articles Next article 
ORIGINAL ARTICLE
Adv Biomed Res 2017,  6:163

Effect of Genistein and 17-β Estradiol on the Viability and Apoptosis of Human Hepatocellular Carcinoma HepG2 cell line


1 Departments of Anatomical Sciences, Jahrom University of Medical Sciences, Jahrom, Iran
2 Department of the Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran

Date of Web Publication26-Dec-2017

Correspondence Address:
Dr. Fraidoon Kavoosi
Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Fars Province
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/abr.abr_53_17

Rights and Permissions
  Abstract 


Background: One of the most lethal cancers is hepatocellular carcinoma (HCC). Genistein (GE) is a choice compound for treatment of certain types of cancer. Phytoestrogens are plant derivatives that bear a structural similarity to 17-β estradiol (E2) and act in a similar manner. They are a group of lipophillic plant compounds with tumorigenic and antitumorigenic effects. E2 has stimulatory and inhibitory effects on cancer cell lines. This study was designed to investigate the antiproliferative and apoptotic effects of GE and E2 on the HCC HepG2 cell line. Materials and Methods: HepG2 cells were cultured and treated with various concentrations of GE and E2 and then 3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromideand flow cytometry assay were performed to determine cell viability and apoptosis. Results: GE and E2 induced apoptosis and inhibited cell growth significantly. Reduction of cell viability by 50% required 20 μM E2 for E2-treatment groups and 20 μMGE for GE-treatment groups. The percentage of the GE-treated apoptotic cells was reduced by about 35%, 42%, and 47% (P < 0.001) and that of E2-treated groups 34%, 39%, and 42% (P < 0.001) after 24, 48, and 72 h, respectively. Conclusions: Our experimental work clearly demonstrated that GE and E2 exhibited significant antiproliferative and apoptotic effects on human HCC HepG2 cells.

Keywords: 17-β estradiol, apoptosis, genistein, hepatocellular carcinoma, proliferation


How to cite this article:
Sanaei M, Kavoosi F, Pourahmadi M, Moosavi SN. Effect of Genistein and 17-β Estradiol on the Viability and Apoptosis of Human Hepatocellular Carcinoma HepG2 cell line. Adv Biomed Res 2017;6:163

How to cite this URL:
Sanaei M, Kavoosi F, Pourahmadi M, Moosavi SN. Effect of Genistein and 17-β Estradiol on the Viability and Apoptosis of Human Hepatocellular Carcinoma HepG2 cell line. Adv Biomed Res [serial online] 2017 [cited 2019 Mar 22];6:163. Available from: http://www.advbiores.net/text.asp?2017/6/1/163/221411




  Introduction Top


One of the most lethal cancers is hepatocellular carcinoma (HCC).[1] The cancer is a slow process during which genetic and epigenetic changes progressively alter the genes expression evolving in prevention of HCC and is chemoresistant to most currently available chemotherapeutic agents. Liver cancer is one of the most common causes of cancer deaths worldwide and the incidence of this fatal disease is correlated with the presence of infection with hepatitis viruses.[2] Genistein (GE), an isoflavinoid in soy beans, is a choice compound for treatment of certain types of cancer such as gastric cancer, prostate cancer, breast cancer, and colon cancer.[3] In the previous studies, we reported that GE can induce apoptosis in PLC/PRF5 and HepG2 HCC cell lines.[4],[5] Phytoestrogens, a group of natural compound, have estrogen-like activity and similar structure to estradiol (E2) originating from various plant sources include fruits, soy beans, vegetables, legumes, and flax seeds. These compounds are phenolic nonsteroidal plant-derived compounds possessing estrogen-like activity.[6] Phytoestrogens are plant derivatives that bear a structural similarity to E2 and act in a similar manner. They are a group of lipophillic plant compounds with tumorigenic and anti-tumorigenic effects [7] that demonstrate weak estrogenic and antiestrogenic activity in different tissues. Really, their tumorigenic and antitumorigenic effects depend on their concentrations.[8]

Many studies have demonstrated that E2 has stimulatory effect on the proliferation of human WRO, FRO, and ARO thyroid carcinoma cells.[9] Other results have shown that E2 significantly increases apoptosis in prostate, MDA-MB-231 breast, colorectal and pancreatic cancers.[10],[11] Our previous work indicated that E2 can inhibit proliferation and induce apoptosis in PLC/PRF5 HCC cells.[12] However, only limited studies are available to report the effects of GE associated with E2 on HCC HepG2 cells. This study was designed to investigate the antiproliferative and apoptotic effect of GE and E2 on the HCC HepG2 cell line.


  Materials and Methods Top


Materials

HepG2 cells were purchased from the National Cell Bank of Iran-Pasteur Institute. Dulbecco minimal essential medium (DMEM), 17-β E2, GE, AnnexinV-FITC, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) were purchased from Sigma (Sigma, St. Louis, MO, USA). All other compounds including fetal bovine serum (FBS) (product number f2442), penicillin (CAS number 69-57-8), and streptomycin (CAS number 3810-74-0) obtained from sigma too. 17-β estradiol and GE were dissolved in dimethyl sulfoxide (DMSO); DMSO was present at 0.01%–0.3%.

Cell culture and treatment

As mentioned above, HepG2 cells were purchased from the National Cell Bank of Iran-Pasteur Institute and cultured in Dulbecco's Modified Eagle Medium (DMEM). All experimental media were supplemented with 10% FBS, penicillin (100 IU/ml) and streptomycin (100 μg/ml). The HepG2 cells were incubated at 37°C, 95% humidity, 5% CO2. When HepG2 cells became >80% confluent, 5 × 105 cells were cultured into 24-well plates (Becton-Dickinson) for 24 h in culture medium before they were incubated with certain concentrations of E2 (1, 5, 10, 25, 50, 75, and 100 μM) and GE (1, 5, 10, 25, 50, 75, and 100 μM) dissolved in DMSO. It should be noted that the control groups were treated with DMSO only. The proliferative effects of certain concentrations of GE and E2 (as mentioned) were assessed by MTT assay, according to the standard protocols. After 24, 48, and 72 h of treatment, the HepG2 cells were washed twice with phosphate-buffered saline, and then a fresh medium containing MTT (0.5 mg/mL) was added. After 4 h, the formazan crystals were dissolved in acidic isopropanol and the absorbance was measured at 540 nm. All experiments of the all groups were repeated three times, with at least three measurements (triplicates).

Determination of apoptotic cells by flow cytometry assay

Human HCC HepG2 cells were seeded in 24-well plates. After 24 h of culture time, the medium-free chemical was changed with medium contains 20 μM E2 (in the three groups) and 20 μM GE (in the other three groups), obtained average dose as means of 24, 48, and 72 h. Flow cytometry assay was down after 24, 48, and 72 h of treatment. Besides, two groups were received combined drugs; first treated with GE (20 μM) and after 24 h treated with E2 (20 μM) and finally 24 and 48 h after treated with E2 flow cytometry assay was down. In this method, all the HepG2 adherent cells were trypsinized by 0.05% trypsin and then Annexin-V-(FITC) and propidium iodide (PI, Becton-Dickinson, San Diego, CA, USA) were used for staining of collected cells according to the manufacturer's instructions. The double-stained HepG2 cells were analyzed by a FACSCanto flow cytometer (Becton-Dickinson, Mountain View, CA, USA). All experiments of this study were processed independently three times. In each experiment, a minimum of 5 × 105 cell/ml were analyzed.

Statistical analysis

The database was setup with the SPSS 16.0 software package for analysis. The data were acquired from three tests and are shown as means ± standard deviations. Statistical comparisons between groups were performed with ANOVA (one-way ANOVA) and Tukey's test. A significant difference was considered P < 0.05.


  Results Top


Result of the MTT assay

The proliferative effects of GE and E2 with different concentrations (as mentioned above) in 24, 48, and 72 h were analyzed using the MTT assay. The amounts of reduced MTT in the all experimental groups were significantly lower than that of the control groups (P < 0.001). E2 inhibited growth in all treated groups by 88%–32% at 24 h, 82%–30% at 48 h, and 72%–22% at 72 h (P < 0.001) and also GE inhibited growth in all treated groups by 80%–30% at 24 h, 72%–24% at 48 h, and 64%–18% at 72 h (P < 0.001). Reduction of cell viability by 50% (IC50) required 20 μM E2 for E2-treatment groups and 20 μM GE for GE-treatment groups. These IC50 doses of GE and E2 are average doses of different time periods (24, 48, and 72 h). For consistency of the result, each experiment was repeated three times [Figure 1].
Figure 1: The cell vitality in the cells which treated with genistein and estradiol at mentioned concentration in different time periods (24, 48 and 72 h) analyzed by using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. In each group from left to right, first column belongs to control and others belong to 1, 5, 10, 25, 50, 75 and 100 μ M concentrations respectively. The amounts of reduced 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide in the all experimental groups were significantly lower than that of the control groups (P < 0.001)

Click here to view


Result of the apoptosis assay

The HepG2 cells were treated with alone and combined drugs, 20 μM E2 and 20 μM GE (obtained average dose as means of 24, 48, and 72 h), for different time periods (24, 48, and 72 h) and flow cytometry was performed to determine the apoptotic cells. As shown in [Figure 2], flow cytometry revealed that GE and E2 (alone and combined) induced significant apoptosis versus control group. Maximal apoptosis induction was observed in the group which received GE (24 h) and then E2 (48 h) and minimal apoptosis induction was observed in the group which received E2 alone for 24 h.
Figure 2: Effect of genistein and estradiol on HepG2 cells apoptosis. The cells were treated with genistein (20 μ M) and estradiol (20 μ M) for 24, 48 and 72 h and the apoptosis- inducing effect were investigated by flow cytometric analysis of HepG2 cells stained with Annexin V and propidium iodide. Genistein and estradiol (alone and combined) induced significant apoptosis in the all treated groups versus control group (P < 0.001), 95% confidence interval

Click here to view


The percentage of GE-treated apoptotic cells were reduced by about 35, 42, and 47% (P < 0.001) and that of E2-treated groups 34, 39, and 42% (P < 0.001) after 24, 48, and 72 h, respectively. In the flow cytometry graph, the right lower quadrant was considered as primary apoptotic cells and the right upper quadrant as secondary apoptotic cells. Maximal apoptotic cell (62%, P < 0.001) was observed in the group which received GE for 24 h and then E2 for 48 h and minimal apoptotic cell (35%, P < 0.001) was observed in the group which received E2 alone for 24 h [Figure 2] and [Figure 3].
Figure 3: Effect of genistein on HepG2 cells apoptosis. Maximal apoptotic cell was observed in the group which received genistein for 24 h and then estradiol for 48 h and minimal apoptotic cell was observed in the group which received E2 alone for 24 h

Click here to view



  Discussion Top


HCC is a global health problem and one of the most causes of cancer-related death. Chronic hepatitis B and C are well-recognized risk factors of HCC. GE, a flavonoid and a bioactive component of soy isoflavones, is a potent apoptosis inducer of human cancers. Experimental and epidemiologic studies have reported that soyfoods prevent cancer and induce apoptosis in many different organs. Many researchers have indicated that the isoflavonoid GE is one of the most components responsible for apoptosis in different cancers.[13] Phytoestogens, one group of plant compounds, have estrogenic effects in animals; both tumorigenic and antitumorigenic effects have been reported. Regulation of the growth and differentiation of many tissues are one of the actions of the estrogens and these compounds can act as mitogen.[14] It have been demonstrated that material nutrition rich in phytoestrogen can influence cancer development and cancer inhibition.[15]

Our experimental work showed that E2 and GE (alone and combined) can inhibit proliferation of HepG2 cell and induce apoptosis in this cell line. Significant inhibitory and apoptotic effects of GE on the HepG2 cell have been reported in the other works [14] and also same effects of E2 on the PLC/PRF5 cell line.[12] Therefore, in this work, we evaluated the effects of E2 and GE (alone and combined) on HepG2 cell line. We expected agonistic effect of E2 in this work, but it showed antagonistic effect in this cell line. Similar study has been reported that GE has apoptotic and antiproliferative effect in MDA-MB-435 and MDAMB-231 breast cancer cell line.[16] Antimetastatic effect of GE on the prostate cancer cell has been reported by other researchers too.[17] Similarly, apoptotic effect of E2 on prostate and colorectal cancer cell has been shown.[11]

In vivo study has been shown that E2 induces apoptosis in prostatic cancer in the rat.[18] GE can induce apoptosis by different mechanisms. One of the mechanisms by which GE acts is upregulation of p21 and downregulation of PLK-1 reported in LNCaP and PC-3 cells.[19] There are various experimental evidences showing that GE is a protein tyrosine kinase inhibitor [20] and inhibits cancer cell growth by modulation of the genes, which involve in apoptosis. It has been reported that GE inhibits Nuclear factor-kappa B (NF-κB) and Akt signaling pathways which play an important role in the cell viability.[21] It can inhibit transcription of the NF-κB-dependent genes by preventing NF-κB from binding to its target DNA.[22] It has demonstrated that GE induces apoptosis by Bcl-2 and Bax induction in estrogen receptor (ER)-positive MCF-7 cells.[23] Various pathways have been reported for apoptotic effect of E2. Experimental works have been indicated that E2 potentiates prostaglandin J2 (PGJ2)-induced apoptosis in breast cancer MCF-7 cell and has an additive effect on PGJ2-induced cell apoptosis.[24] E2 induces apoptosis through intrinsic pathway of mitochondrial disruption and release of cytochrome C.[25] Activation of the Fas/FasL pathways has been reported as a mechanism by which E2 induces apoptosis in breast cancer cells.[26] Similarly, a link between estradiol-induced apoptosis and activation of the FasR/FasL death-signaling pathway have been reported.[27] Other researchers have indicated that E2 bind to cell surface proteins resulting in calcium reflux and activation of adenylate cyclase and phospholipase C and finally cAMP and IP3 generation and also demonstrated that stimulation/inhibition (dependent on the ER subtype) of phosphoinositol-3 hydroxy kinase and the family of mitogen-activated protein kinases, such as p38β isoform and c-Jun N-terminal kinase (JNK) are rapidly responsive to E2 that regulate migration, angiogenesis, and apoptosis through nuclear compartments.[28],[29],[30],[31]

The above-mentioned reports support our result. Opposite to our report, it has been shown that E2 stimulates proliferation of prostate stromal cells (PrSCs).[32]

Proliferative effect of E2 on breast cancer MCF-7 cells, human colon carcinoma HT-29 and Caco-2 cells lines have been reported too.[33]

On the contrary to our report, several studies have reported that E2 has proliferative effect, E2 induces proliferation in gastric cancer cell [34] and also accelerates ER-negative breast cancer metastasis and increases metastatic tumor and colony formation in the lungs in mice.[35] Similar work has indicated that E2 stimulates proliferation of primary prostate stromal cells (PrSCs and WPMY-1)[32] and human breast epithelial cell MCF-10F.[36] In the present study, we reported apoptotic effect for GE but just the opposite several studies have demonstrated proliferative effect for this compound. It has been reported that GE stimulates the proliferation of MCF-7 and T47D breast cancer cells [37] and also MCF7wt and MCF7SH breast cancer cells.[38] This compound has proliferative effect on mammary gland too.[39]In vivo study has demonstrated that GE accelerates prostate cancer progression in TRAMP-FVB mice.[40] Finally, these compounds have biphasic effects and can inhibit proliferation or induce apoptosis according to dose, time, and tissue. In this work, we did not related experiments about acetylation and methylation involved in apoptosis.


  Conclusions Top


Our result suggests that E2 and GE (alone and combined) may be a potent anticarcinogenic compounds and can effectively inhibit proliferation and induce apoptosis in HepG2 cells.

Acknowledgments

We thank members of our groups for helpful comments and discussion.

Financial support and sponsorship

This article was supported by adjutancy of research of Jahrom medical University-Iran.

Conflicts of interest

There are no confl icts of interest.



 
  References Top

1.
Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer 2006;6:674-87.  Back to cited text no. 1
[PUBMED]    
2.
Nishida N, Goel A. Genetic and epigenetic signatures in human hepatocellular carcinoma: A systematic review. Curr Genomics 2011;12:130-7.  Back to cited text no. 2
[PUBMED]    
3.
Spagnuolo C, Russo GL, Orhan IE, Habtemariam S, Daglia M, Sureda A, et al. Genistein and cancer: Current status, challenges, and future directions. Adv Nutr 2015;6:408-19.  Back to cited text no. 3
[PUBMED]    
4.
Sanaei M, Kavoosi F, Arezoo M. Apoptotic effect of genistein on hepatocellular carcinoma HepG2 cell line. Glob J Med Res Stud 2016;3:1-8.  Back to cited text no. 4
    
5.
Dastjerdi MN, Kavoosi F, Valiani A, Esfandiari E, Sanaei M, Sobhanian S, et al. Inhibitory effect of genistein on PLC/PRF5 hepatocellular carcinoma cell line. Int J Prev Med 2015;6:54.  Back to cited text no. 5
[PUBMED]  [Full text]  
6.
Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor a (ERa) and ERb in human cells. Toxicol Sci 2004;80:14-25.  Back to cited text no. 6
[PUBMED]    
7.
Oseni T, Patel R, Pyle J, Jordan VC. Selective estrogen receptor modulators and phytoestrogens. Planta Med 2008;74:1656-65.  Back to cited text no. 7
[PUBMED]    
8.
Jeng YJ, Watson CS. Proliferative and anti-proliferative effects of dietary levels of phytoestrogens in rat pituitary GH3/B6/F10 cells – The involvement of rapidly activated kinases and caspases. BMC Cancer 2009;9:334.  Back to cited text no. 8
[PUBMED]    
9.
Vivacqua A, Bonofiglio D, Albanito L, Madeo A, Rago V, Carpino A, et al. 17beta-estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol Pharmacol 2006;70:1414-23.  Back to cited text no. 9
[PUBMED]    
10.
Rajah TT, Peine KJ, Du N, Serret CA, Drews NR. Physiological concentrations of genistein and 17ß-estradiol inhibit MDA-MB-231 breast cancer cell growth by increasing BAX/BCL-2 and reducing pERK1/2. Anticancer Res 2012;32:1181-91.  Back to cited text no. 10
[PUBMED]    
11.
Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P. Dietary phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr 2006;136:3046-53.  Back to cited text no. 11
[PUBMED]    
12.
Nikbakht Dastjerdi M, Kavoosi F. Inhibitory effect of 17-beta estradiol on hepatocellular carcinoma cell line. Indian J Appl Res 2015;5:435-9.  Back to cited text no. 12
    
13.
Zava DT, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutr Cancer 1997;27:31-40.  Back to cited text no. 13
[PUBMED]    
14.
Pike MC, Pearce CL, Wu AH. Prevention of cancers of the breast, endometrium and ovary. Oncogene 2004;23:6379-91.  Back to cited text no. 14
[PUBMED]    
15.
Mense SM, Hei TK, Ganju RK, Bhat HK. Phytoestrogens and breast cancer prevention: Possible mechanisms of action. Environ Health Perspect 2008;116:426-33.  Back to cited text no. 15
[PUBMED]    
16.
Li Y, Bhuiyan M, Sarkar FH. Induction of apoptosis and inhibition of c-erbB-2 in MDA-MB-435 cells by genistein. Int J Oncol 1999;15:525-33.  Back to cited text no. 16
[PUBMED]    
17.
Marino M, Galluzzo P, Leone S, Acconcia F, Ascenzi P. Nitric oxide impairs the 17beta-estradiol-induced apoptosis in human colon adenocarcinoma cells. Endocr Relat Cancer 2006;13:559-69.  Back to cited text no. 17
[PUBMED]    
18.
Cheng J, Lee EJ, Madison LD, Lazennec G. Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis. FEBS Lett 2004;566:169-72.  Back to cited text no. 18
[PUBMED]    
19.
Seo YJ, Kim BS, Chun SY, Park YK, Kang KS, Kwon TG. Apoptotic effects of genistein, biochanin-A and apigenin on LNCaP and PC-3 cells by p21 through transcriptional inhibition of polo-like kinase-1. J Korean Med Sci 2011;26:1489-94.  Back to cited text no. 19
[PUBMED]    
20.
Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncol 2002;3:364-73.  Back to cited text no. 20
[PUBMED]    
21.
Li Y, Sarkar FH. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 2002;8:2369-77.  Back to cited text no. 21
[PUBMED]    
22.
Banerjee S, Li Y, Wang Z, Sarkar FH. Multi-targeted therapy of cancer by genistein. Cancer Lett 2008;269:226-42.  Back to cited text no. 22
[PUBMED]    
23.
Leung LK, Wang TT. Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J Nutr 2000;130:2922-6.  Back to cited text no. 23
[PUBMED]    
24.
Yaacob NS, Nasir R, Norazmi MN. Influence of 17ß-estradiol on 15-deoxy-d12,14 prostaglandin J2 -induced apoptosis in MCF-7 and MDA-MB-231 cells. Asian Pac J Cancer Prev 2013;14:6761-7.  Back to cited text no. 24
[PUBMED]    
25.
Song RX, Mor G, Naftolin F, McPherson RA, Song J, Zhang Z, et al. Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 2001;93:1714-23.  Back to cited text no. 25
[PUBMED]    
26.
Song RX, Santen RJ. Apoptotic action of estrogen. Apoptosis 2003;8:55-60.  Back to cited text no. 26
[PUBMED]    
27.
Lewis JS, Meeke K, Osipo C, Ross EA, Kidawi N, Li T, et al. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J Natl Cancer Inst 2005;97:1746-59.  Back to cited text no. 27
[PUBMED]    
28.
Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006;116:561-70.  Back to cited text no. 28
[PUBMED]    
29.
Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 2001;12:152-6.  Back to cited text no. 29
[PUBMED]    
30.
Levin ER. Cellular functions of plasma membrane estrogen receptors. Steroids 2002;67:471-5.  Back to cited text no. 30
[PUBMED]    
31.
Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407:538-41.  Back to cited text no. 31
[PUBMED]    
32.
Zhang Z, Duan L, Du X, Ma H, Park I, Lee C, et al. The proliferative effect of estradiol on human prostate stromal cells is mediated through activation of ERK. Prostate 2008;68:508-16.  Back to cited text no. 32
[PUBMED]    
33.
Di Domenico M, Castoria G, Bilancio A, Migliaccio A, Auricchio F. Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. Cancer Res 1996;56:4516-21.  Back to cited text no. 33
[PUBMED]    
34.
Kameda C, Nakamura M, Tanaka H, Yamasaki A, Kubo M, Tanaka M, et al. Oestrogen receptor-alpha contributes to the regulation of the hedgehog signalling pathway in ERalpha-positive gastric cancer. Br J Cancer 2010;102:738-47.  Back to cited text no. 34
[PUBMED]    
35.
Yang X, Belosay A, Du M, Fan TM, Turner RT, Iwaniec UT, et al. Estradiol increases ER-negative breast cancer metastasis in an experimental model. Clin Exp Metastasis 2013;30:711-21.  Back to cited text no. 35
[PUBMED]    
36.
Russo J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, et al. 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. FASEB J 2006;20:1622-34.  Back to cited text no. 36
[PUBMED]    
37.
Seo HS, DeNardo DG, Jacquot Y, Laïos I, Vidal DS, Zambrana CR, et al. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat 2006;99:121-34.  Back to cited text no. 37
    
38.
Maggiolini M, Bonofiglio D, Marsico S, Panno ML, Cenni B, Picard D, et al. Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol Pharmacol 2001;60:595-602.  Back to cited text no. 38
[PUBMED]    
39.
Foth D, Cline JM. Effects of mammalian and plant estrogens on mammary glands and uteri of macaques. Am J Clin Nutr 1998;68 6 Suppl:1413S-7S.  Back to cited text no. 39
    
40.
El Touny LH, Banerjee PP. Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res 2009;69:3695-703.  Back to cited text no. 40
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
Previous article  Next article
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusions
References
Article Figures

 Article Access Statistics
    Viewed721    
    Printed14    
    Emailed0    
    PDF Downloaded84    
    Comments [Add]    

Recommend this journal