Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERα and HER2/neu.
Journal: 2015/October - Acta Naturae
ISSN: 2075-8251
PUBMED: 26483970
Abstract:
Phytoestrogens are a group of plant-derived compounds with an estrogen-like activity. In mammalians, phytoestrogens bind to the estrogen receptor (ER) and participate in the regulation of cell growth and gene transcription. There are several reports of the cytotoxic effects of phytoestrogens in different cancer cell lines. The aim of this study was to measure the phytoestrogen activity against breast cancer cells with different levels of ER expression and to elucidate the molecular pathways regulated by the leader compound. Methods used in the study include immunoblotting, transfection with a luciferase reporter vector, and a MTT test. We demonstrated the absence of a significant difference between ER+ and ER- breast cancer cell lines in their response to cytotoxic stimuli: treatment with high doses of phytoestrogens (apigenin, genistein, quercetin, naringenin) had the same efficiency in ER-positive and ER-negative cells. Incubation of breast cancer cells with apigenin revealed the highest cytotoxicity of this compound; on the contrary, naringenin treatment resulted in a low cytotoxic activity. It was shown that high doses of apigenin (50 μM) do not display estrogen-like activity and can suppress ER activation by 17β-estradiol. Cultivation of HER2-positive breast cancer SKBR3 cells in the presence of apigenin resulted in a decrease in HER2/neu expression, accompanied by cleavage of an apoptosis substrate PARP. Therefore, the cytotoxic effects of phytoestrogens are not associated with the steroid receptors of breast cancer cells. Apigenin was found to be the most effective phytoestrogen that strongly inhibits the growth of breast cancer cells, including HER2-positive ones.
Relations:
Content
Citations
(6)
References
(41)
Drugs
(1)
Similar articles
Articles by the same authors
Discussion board
Acta Naturae. Dec/31/2014; 7(3): 133-139

Apigenin Inhibits Growth of Breast Cancer Cells: The Role of ERα and HER2/neu

Abstract

INTRODUCTION

Breast cancer is the most common cancer in females, ranking second in theincidence rate after skin neoplasms in the Russian population [1-4]. Thesearch for new prospective compounds that could inhibit the development ofbreast cancer and the analysis of their impact on tumor cells is one of thepriorities in oncology. Given the important role of hormones in the developmentof reproductive system tumors, compounds structurally similar to estrogens,e.g., phytoestrogens, are of particular interest. Phytoestrogens areplant-derived compounds with steroid-like structures [5]. Because of their “hormonal” properties,phytoestrogens are also referred to as “food hormones.”Phytoestrogens are unique in their paradoxical effect on cells: depending onthe conditions, they can either inhibit tumor growth or act as cell protectors[5-7].

Initially, interest in phytoestrogen research arose from the analysis ofepidemiological data showing a reduced rate of tumor incidence and cancermortality in a number of geographical areas with high consumption of fruits andvegetables [8-10].A study by Knekt et al. [8],which was conducted in Finland, included9,959 individuals who were followed from 1967 to 1991 and whose individualconsumption of phytoestrogens with food was analyzed. A total of 997 cases ofcancer (ca. 10% of the complete sample) were identified over the entire periodof the study, including 151 cases of lung cancer. A statistical analysis showedthat the relative risk of cancers (all localizations) in a group with highconsumption of phytoestrogens was reduced to 0.8 (the risk level in a groupwith low consumption of phytoestrogens was taken as 1). The most significantresults were obtained upon analysis of the incidence rate of lung cancer; therisk dropped to 0.54 in the group with high consumption of phytoestrogens[8]. Similar tendencies were found uponexamination of 1,031 ovarian cancer females and 2,411 healthy donors in Italyover a period between 1992 and 1999 [11]. According to Rossi et al. [11], the risk of ovarian cancer dropped to0.63 in the group with high consumption of flavonols (in particular, quercetin)and to 0.51 in the group with high consumption of foods rich in isoflavones(e.g., genistein). Therefore, the epidemiological data indicate theadvisability of increased consumption of foods rich in phytoestrogens toprevent cancer.

However, the epidemiological data do not reveal the molecular mechanisms bywhich phytoestrogens affect tumor cells and/or protect normal cells frommalignant transformation. This is why an extensive search for the mainintracellular targets of these compounds is currently underway in invitro models [12-17]. The key targets of phytoestrogens intumor cells are believed to be receptor tyrosine kinases, including theepidermal growth factor receptor (EGFR) [18-20], fibroblastgrowth factor receptor 2 (FGFR2) [21],HER2/ neu [22], vascular endothelialgrowth factor receptor 3 (VEGFR3) [21,23], the platelet-derived growth factorreceptor alpha and beta (PDGFRα and s) [21], etc. In addition to receptors, some members of thephytoestrogen class effectively inhibit the intracellular kinases involved inthe regulation of cell proliferation and cell survival, such as p21-activatedkinase 3 (PAK3), phosphatidylinositol 3-kinase (PI3K), Akt, PIM1, Aurora-A,Janus kinase 3 (JAK3), etc. [15, 16, 21]. The wide range of the potential targets of phytoestrogensmakes these compounds promising for further experimental and clinical studies.

Is the estrogen receptor (ER) required for the antiproliferative effect ofphytoestrogens on tumor cells, and is the hormone-like effect of phytoestrogensconcentration- dependent? There is no definite answer to these questions [5, 6,17]. The aim of this study was toinvestigate the effect of members of the main groups of phytoestrogens onbreast cancer cells with various ER statuses and to analyze the molecularpathways responsible for the antiproliferative and cytotoxic effects of aleader compound. Using human breast cancer cell lines, we demonstrated that theantiproliferative effect of high doses of phytoestrogens (apigenin, genistein,quercetin, naringenin) did not depend on the status of steroid hormonereceptors. In vitro experiments revealed a similar efficacy ofthese compounds in a ER-positive MCF-7 cell line and ER-negative SKBR3 model.The maximum antiproliferative effect was observed for flavone apigenin that wasanalyzed in more detail as the leader compound. An increase in apigeninconcentrations from 5 to 50 μM in MCF-7 cells was demonstrated to resultin a “switch” from estrogen-like (similar to the effect of17β-estradiol, a natural ligand of ERα) to anti-estrogenic effects(similar to the effect of antiestrogen drugs): a high apigenin dose inhibitedactivation of estrogen receptors by 17β-estradiol. ERnegative SKBR3 breastcancer cells are known to be characterized by a high level of HER2/neu, one ofthe key receptors defining the high aggressiveness and survival of tumor cells[24]. Immunoblotting demonstrated thatapigenin at a dose of above 25 μM reduces the expression of HER2/neu inSKBR3 cells, with a simultaneous degradation of the apoptosis effect orsubstrate poly ADP-ribose polymerase (PARP). Apigenin was the most promisingamong the tested compounds, demonstrating significant inhibition of growth ofbreast cancer cells with various ERα statuses, including HER2-positiveones.

MATERIALS AND METHODS

Fig. 1
Chemical structures of phytoestrogens (apigenin, naringenin, genistein,quercetin)

Phytoestrogens from various groups were studied: apigenin (flavone), naringenin(flavanone), genistein (isoflavone), and quercetin (flavonol). Quercetin,genistein, and naringenin were purchased from Sigma-Aldrich (USA), apigenin wasfrom Enzo Biochem (USA); the chemical purity of each compound was at least 97%.The chemical structures of the compounds are shownin Fig. 1.The compounds were dissolved in dimethylsulfoxide at a concentration of 50 mM,and the solutions were stored until use at –20°C.

Human breast cancer cells MCF-7 (ERα+/HER2–) and SKBR3(ERα–/HER2+) were obtained from the collection of the Blokhin N.N.Russian Cancer Research Center. The cell lines were cultured in vitroin a standard DMEM medium (Biolot, Russia) with 10% fetal calf serum(HyClone, USA) and gentamycin (50 U/mL, PanEco, Russia) at 37 °C, 5% ofCO2, and a relative humidity of 80–90%. The cell growth ratewas determined using a MTT assay, based on the uptake of the MTT reagent(3-[4,5-dimethylthiazol-2]-2,5-diphenyltetrazolium bromide) by the living cells[25, 26].

To determine the transcriptional activity of ERα, the cells weretransfected with a plasmid containing the luciferase reporter gene under thecontrol of an ERsensitive promoter (ERE/Luc); the plasmid was a kind gift fromGeorge Reid (European Molecular Biology Laboratory, Germany)[27]. The cells were transfected using aMetafectene® PRO reagent according to the manufacturer’srecommendations (Biontex Laboratories, Germany). The efficacy and potentialtoxicity of the transfection was monitored by co-transfection of the cells witha plasmid containing the β-galactosidase gene. The luciferase activity wascalculated in arbitrary units (ratio of the total luciferase activity to thegalactosidase activity in samples).

For immunoblotting purposes, the cells at 80% confluency were detached from thedishes (60 mm, Corning, USA) into 1 mL of a phosphate buffer. To obtain a totalcell extract, samples were added with 130 μL of the following buffer: 50mM Tris-HCl pH 7.4, 1% SDS (sodium dodecyl sulfate), 1% Igepal CA-630, 0.25% Nadeoxycholate, 150 mM NaCl, 1 mM EDTA (ethylenediaminetetraacetic acid), 1 mMPMSF (phenylmethanesulfonyl fluoride); 1 μg/mL of aprotinin, leupeptin,and pepstatin; and 1 mM Na orthovanadate and 1 mM NaF. Total cell extracts weresonicated on a SoniPrep 150 Plus disintegrator (MSE) (five cycles of 10 s eachwith an amplitude of 3.2) to reduce the viscosity of a solution. Cell extractsamples were then centrifuged (10,000 g, 10 min, +4oC,Eppendorf 5417R centrifuge, Germany), and standard electrophoresis andimmunoblotting procedures were performed. The levels of HER2/neu and PARP weredetermined by primary antibodies (Cell Signaling Technology, USA). Antibodiesto β-actin (Cell Signaling Technology, USA) were used to monitor theeffectiveness of immunoblotting and to normalize the results. Detection wasperformed using secondary horseradish peroxidase-conjugated antibodies (JacksonImmunoResearch, USA) in the LAS 4000 system (GE HealthCare, USA). DATAPLOTsoftware (USA) was used for statistical analysis. In all cases, the statisticalcriteria were considered to be significant at p < 0.05; eachexperiment was performed at least in triplicate.

RESULTS AND DISCUSSION

Comparison of the cytotoxic properties of various groups ofphytoestrogens with respect to breast cancer cells: selection of the leadercompound

Fig. 2

Cytostatic effect of phytoestrogens on breast cancer cells MCF-7 (A) and SKBR3(B). Data of a MTT test conducted after 3-day cell growth in the presence ofphytoestrogens: 1 – naringenin, 2 – genistein, 3 – quercetin,4 – apigenin. The chart shows the number of living cells after treatmentwith phytoestrogens. The number of control cells of an appropriate cell line istaken as 100%. *p < 0.05 compared to the numberof MCF-7 cells survived at an apigenin dose of 50 μM

At the first stage of the study, the antiproliferative effect of high doses ofphytoestrogens was evaluated in the MTT test. ERα-positive cells of theMCF-7 line were seeded onto culture plates, and phytoestrogens apigenin(flavone), naringenin (flavanone), genistein (isoflavone), and quercetin(flavonol) were added after 24 h. 3-day incubation of cells with naringenin wasfound to have almost no antiproliferative effects. Genistein had a strongerproliferative effect and at the dose of 50 μM caused a 40% reduction inthe number of living cells. Quercetin, a member of the flavonol group,exhibited a genistein-like activity. The highest antiproliferative effect wasobserved for apigenin(Fig. 2A)at a concentration of 50 μM (according to the MTT test data,20% of MCF-7 cells compared with the control).

The ERα-negative SKBR3 cell line was used to answer the question of thepossible impact of ERα expression on cell sensitivity to theantiproliferative action of phytoestrogens (at high concentrations). Thedistribution of SKBR3 cells by sensitivity to various phytoestrogens wassimilar to the distribution of ERα-positive MCF-7 cells. Naringenin wasthe least cytotoxic. Genistein and quercetin had a moderate antiproliferativeeffect. The highest antiproliferative activity was observed for apigenin: at aconcentration of 50 μM, it caused the death of 60% of SKBR3 cells (3-dayincubation withphytoestrogens, Fig. 2B).It should be noted that only quercetin (MCF-7 cells) and apigenin (MCF-7 andSKBR3 cells) reached the IC50 level(Table) afterincubation of the cells with the phytoestrogens in the given range of concentrations(up to 50 μM). Therefore, naringenin and genistein are rather “weak”antiproliferative agents, and they should be tested in combination withcompounds from other classes, e.g., antiestrogens of the SERM group (tamoxifen,etc.) and specific inhibitors of tyrosine kinases. Comparison of the number ofviable MCF-7 and SKBR3 cells after 3-day incubation with 50 μM apigenindemonstrated that the SKBR3 line is more resistant to the cytostatic effect ofapigenin than MCF-7 (40 and 20% of cells compared to the control,respectively, p < 0.05). On the basis of this observation,we presumed that high doses of apigenin could inhibit both the estrogenreceptor signaling pathway (important factor for the growth of MCF-7 cells) andreceptor tyrosine kinases, in particular HER2/neu (overexpression of thisreceptor was detected in SKBR3 cells).

Table

IC50 of phytoestrogens

IC50, μMNaringeninGenisteinQuercetinApigenin
MCF-7> 50> 505025
SKBR3> 50> 50> 5030

The results of this series of experiments indicate that apigenin has themaximum antiproliferative effect among the tested phytoestrogens. Therefore, wefurther examined the molecular mechanisms of the action of high doses of thisphytoestrogen on breast cancer cells.

Effect of apigenin on the estrogen receptor activity

Fig. 3

The effect of apigenin on the 17β-estradiolinduced activity of theestrogen receptor. After transfection with a reporter plasmid, MCF-7 cells wereseeded onto 24-well plates and after 24 h were treated with 17β-estradioland apigenin (1 – control MCF-7 cells; 2 – 10 nM17β-estradiol; 3 – 10 nM 17β-estradiol and 5 μM apigenin;4 – 10 nM 17β-estradiol and 50 μM apigenin). The luciferaseactivity was measured after 7 h of cultivation in the presence of thephytoestrogens according to the standard protocol by the reagent’smanufacturer (Promega, USA). *p < 0.05 comparedwith control cells; #p < 0.05 for comparing columns 4and 3

The tendencies discussed in the previous section indicate that theantiproliferative effect of phytoestrogens on breast cancer cells increases astheir concentration increases. It is important to note that this effect isindependent of the hormonal status of cells; however, the ERα-positiveMCF-7 line is more sensitive to the antiproliferative action of high doses ofapigenin (50 μM) than the ERα-negative SKBR3 line. We assumed thatthe increase in the concentration of apigenin is accompanied by a“switching-off” of the hormonal component of its action on breastcancer cells. To test this hypothesis, MCF-7 cells were transfected with aplasmid containing a reporter construct with the luciferase gene under thecontrol of an estrogen-sensitive promoter. The cells were then transferred to aDMEM medium without phenol red (PanEco, Russia) and cultivated with addition ofa 10% steroid-free fetal calf serum (HyClone, USA) for 24 h. The luciferaseactivity was measured after 7 h of cell growth in the presence of17β-estradiol and apigenin. As shownin Fig. 3,lowdose apigenin had an estrogen-like effect and enhanced the inducing effect of17β-estradiol on the estrogen receptor. A 10-fold increase in the apigeninconcentration (to 50 μM) had the opposite effect: the phytoestrogeninhibited the estrogen receptor activity and prevented the action of17β-estradiol. Thus, the anti-estrogenic properties of apigenin may be oneof the explanations for the cytostatic effects of its high (50 μM) doses.These findings partly explain the effect of apigenin on MCF-7 cells: apigeninblocks the main proliferative stimulus for this tumor line. Which“target” does apigenin block in a ERα-negative SKBR3 breastcancer cell line? This issue was examined in the next series of experiments.

Changes in the HER2/neu level during incubation of breast cancer cellswith apigenin

Fig. 4
The effect of apigenin on HER2/neu expression and PARP degradation in SKBR3cells. SKBR3 cells were treated with the apigenin concentrations shown in thefigure for 3 days. The results of one of three independent experiments are shown

The expression of HER2/neu is known to be detected in 10–30% of breastcancers, which is regarded as a marker of poor prognosis[28, 29].We analyzed the effect of apigenin on the HER2/neu expression in SKBR3 cells that producethis protein in sufficient quantities. As seenin Fig. 4,apigenin at concentrations from 3 to 12 μM does not affect the HER2/neulevel in SKBR3 cells. However, incubation of the cells with higher doses ofapigenin (25 and 50 μM) results in significant inhibition of the HER2/neuexpression. Immunoblotting with antibodies to the apoptosis effector substrate,PARP, revealed partial degradation of PARP (identified as accumulation of atruncated 89 kDa form of PARP) upon increasing the apigenin concentration inSKBR3 cells.

The ability of phytoestrogens to lower the HER2/ neu level in tumor cells wasdiscovered by Mai et al. [30] during incubation of the human breast cancer BT-474 cellline (HER2/neu+, ERα+) with 25 μM genistein. In addition, cultivationof BT-474 cells with genistein and an antiestrogen tamoxifen led to a furtherdecrease in the expression of HER2/neu. A similar effect was observed foranother member of the HER receptor family, EGFR (HER1) [30]. The phosphorylation level of HER2/neu and EGFR kinaseswas not analyzed, because the biological effect of genistein in this case wascaused by a decrease in the level of its target protein (rather than by itsactivity). Sakla et al. [31] confirmed the data on the reduction in the HER2/neu level[30] and also showed that even at lowdoses (1 μM) genistein decreases the level of HER2/neu phosphorylation inBT-474 cells. Our data on a decrease in the HER2/ neu level in SKBR3 cells uponincubation with apigenin are consistent with the results obtained in anothercell model (MDA-MB-453 breast cancer line) [32]. It was shown that the phytoestrogens apigenin, luteolin,naringenin, eriodictyol, and hesperetin at high doses (40 μM) causedegradation of HER2/neu in MDA-MB-453 cells. Initiation of apoptosis uponincubation of the cells with apigenin was found to occur through the release ofcytochrome c and activation of caspase 3. Summarizing ourfindings and published data, we conclude that high doses of apigenin reduce theexpression of one of the major tyrosine kinases supporting the growth ofHER2-positive cells and simultaneously initiate apoptotic processes.

CONCLUSIONS

The cytotoxic and antiproliferative effects of phytoestrogens on malignantcells are being extensively studied today [14, 33-38]. The interest in phytoestrogens is largelybased on their natural origin and the relatively low cost of their synthesisand purification. In addition, there are data that support the prospects oftheir use for the prevention of cancer [38, 39]. Our workfocuses on the investigation of the properties of flavone apigenin thatexhibits a high antiproliferative activity in cells with various statuses ofestrogen receptors. At high doses, apigenin was demonstrated to prevent theactivation of the estrogen receptor by 17β-estradiol and cause inhibitionof the HER2/neu expression, accompanied by a degradation of PARP inHER2-positive breast cancer cells. Other apigenin targets were identified inbreast cancer cells, including proteins supporting the growth and survival ofthe tumor: PI3K/ Akt [40], STAT3 [33], NF-κB [34], p53 [34, 41], p21 [41], JAK3 [42], cyclinsD1, D3, and Cdk4 [43]and VEGF [44]. Apparently, apigenin is a multi-targetcompound that triggers breast cancer cell death through the inhibition ofreceptor tyrosine kinases, decreased expression of growth factors, activationof p53, and suppression of key transcription factors. In 2008, a phase IIclinical trial (NCT00609310) of a drug containing 20 mg of apigenin and 20 mgof epigallocatechin gallate in patients with colorectal cancer was registeredon the Clinical- Trials.gov database. The first batch of data from this study,regarding changes in the disease relapse rate in patients treated with amixture of these phytoestrogens, is expected in 2016. No other clinical trialsof apigenin (as an antitumor agent) are currently registered onClinicalTrials.gov. Further investigation of the antitumor activity of apigeninand its synthetic derivatives is quite promising, particularly in relation toHER2- positive breast tumors.

Acknowledgments

The authors would like to thank M.A. Krasil’nikov for the discussion ofthe experimental results and the article and George Reid for providing theERE/LUC plasmid.

This work was funded by grants from the Russian ScienceFoundation (№ 14-15-00362, experiments in section #2) and the RussianFoundation for Basic Research (№ 15-04-02172, experiments in sections #1and 3).

References

  • 1. Voprosy Onkologii.2013593314319MerabishviliV.M.[PubMed]
  • 2. CA Cancer J. Clin.2014644252271DeSantisC.E.LinC.C.MariottoA.B.SiegelR.L.SteinK.D.KramerJ.L.AlteriR.RobbinsA.S.JemalA.[PubMed]
  • 3. CA Cancer J. Clin.20146415262DeSantisC.MaJ.BryanL.JemalA.[PubMed]
  • 4. Moscow: Herzen Moscow Oncology Research Institute, 2015. (In Russian)Malignant tumors in Russia in 2013 (incidence and mortality)2015A.D.Kaprin.V.V.Starinskiy.G.V.Petrova.[Google Scholar]
  • 5. World J. Clin. Oncol.201454705712BilalI.ChowdhuryA.DavidsonJ.WhiteheadS.[PubMed]
  • 6. Front Neuroendocrinol.2010314400419PatisaulH.B.JeffersonW.[PubMed]
  • 7. J. Biol. Chem.2012287433616836178BhukhaiK.SuksenK.BhummaphanN.JanjornK.ThongonN.TantikanlayapornD.PiyachaturawatP.SuksamrarnA.ChairoungduaA.[PubMed]
  • 8. Am. J. Epidemiol.19971463223230KnektP.JarvinenR.SeppanenR.HellovaaraM.TeppoL.PukkalaE.AromaaA.[PubMed]
  • 9. Maturitas.2013762118122MouroutiN.PanagiotakosD.B.[PubMed]
  • 10. Asian Pac. J. Cancer Prev.2014152190859091QuX.L.FangY.ZhangM.ZhangY.Z.[PubMed]
  • 11. Internat. J. Cancer.20081234895898RossiM.NegriE.LagiouP.TalaminiR.Dal MasoL.MontellaM.FranceschiS.La VecchiaC.
  • 12. J. Inorg Biochem.2013127107115SpoerleinC.MahalK.SchmidtH.SchobertR.[PubMed]
  • 13. Exp. Mol. Pathol.2014972211217HarrisonM.E.Power CoombsM.R.DelaneyL.M.HoskinD.W.[PubMed]
  • 14. Scanning.2014366622631BaiH.JinH.YangF.ZhuH.CaiJ.[PubMed]
  • 15. Nutr. Cancer.2015672354363MauryaA.K.VinayakM.[PubMed]
  • 16. Anticancer Agents Med. Chem.201515(9)11851189LiS.Z.QiaoS.F.ZhangJ.H.LiK.[PubMed]
  • 17. Climacteric.201518(4)574581ChenF.P.ChienM.H.ChernI.Y.[PubMed]
  • 18. Molecules.201419111855818573GrucaA.KrawczykZ.SzejaW.GrynkiewiczG.RusinA.[PubMed]
  • 19. Cancer.20091151021652176GadgeelS.M.AliS.PhilipP.A.WozniakA.SarkarF.H.[PubMed]
  • 20. Food Funct.201451026322645FirdousA.B.SharmilaG.BalakrishnanS.RajaSinghP.SuganyaS.SrinivasanN.ArunakaranJ.[PubMed]
  • 21. Internat. J. Oncol.2011383833842BolyR.GrasT.LamkamiT.GuissouP.SerteynD.KissR.DuboisJ.
  • 22. J. Agric. Food Chem.2013612664306445HuangC.LeeS.Y.LinC.L.TuT.H.ChenL.H.ChenY.J.HuangH.C.[PubMed]
  • 23. Chinese journal of cellular and molecular immunology.2009258678680YuZ.J.HeL.Y.ChenY.WuM.Y.ZhaoX.H.WangZ.Y.[PubMed]
  • 24. Int. J. Cancer.20051163359367LongvaK.E.PedersenN.M.HaslekasC.StangE.MadshusI.H.[PubMed]
  • 25. Arzneimittelforschung.1989397747749IseltM.HolteiW.HilgardP.[PubMed]
  • 26. Eur. J. Cancer.199228A8-914521458MerlinJ.L.AzziS.LignonD.RamacciC.ZeghariN.GuilleminF.[PubMed]
  • 27. Molecular Cell2003113695707ReidG.HubnerM.R.MetivierR.BrandH.DengerS.ManuD.BeaudouinJ.EllenbergJ.GannonF.[PubMed]
  • 28. Breast Cancer (Auckl).20148109118BrufskyA.M.[PubMed]
  • 29. JAMA.20062952124922502CareyL.A.PerouC.M.LivasyC.A.DresslerL.G.CowanD.ConwayK.KaracaG.TroesterM.A.TseC.K.EdmistonS.[PubMed]
  • 30. Mol. Carcinogenesis.2007467534542MaiZ.BlackburnG.L.ZhouJ.R.
  • 31. Endocrine.20073216978SaklaM.S.ShenoudaN.S.AnsellP.J.MacdonaldR.S.LubahnD.B.[PubMed]
  • 32. FEBS Lett.20055791145152WayT.D.KaoM.C.LinJ.K.[PubMed]
  • 33. Anticancer Res.201434628692882SeoH.S.KuJ.M.ChoiH.S.WooJ.K.JangB.H.ShinY.C.KoS.G.[PubMed]
  • 34. Mol. Cell Biochem.20123661-2319334SeoH.S.ChoiH.S.KimS.R.ChoiY.K.WooS.M.ShinI.WooJ.K.ParkS.Y.ShinY.C.KoS.G.[PubMed]
  • 35. Pharmacogn. Rev.2014816122146SakK.[PubMed]
  • 36. Pharm. Res.2010276962978ShuklaS.GuptaS.[PubMed]
  • 37. World J. Clin. Oncol.201454705712BilalI.ChowdhuryA.DavidsonJ.WhiteheadS.[PubMed]
  • 38. Lab. Anim. Res.2014304143150KimS.H.KimC.W.JeonS.Y.GoR.E.HwangK.A.ChoiK.C.[PubMed]
  • 39. Anticancer Agents Med. Chem.201313811781187DouglasC.C.JohnsonS.A.ArjmandiB.H.[PubMed]
  • 40. Toxicol. Appl. Pharmacol.20082262178191LeeW.J.ChenW.K.WangC.J.LinW.L.TsengT.H.[PubMed]
  • 41. Nutr. Res.2011312139146SeoH.S.JuJ.H.JangK.ShinI.[PubMed]
  • 42. J. Mol. Biol.20134254755766YeQ.KantonenS.Gomez-CambroneroJ.[PubMed]
  • 43. FEBS Lett.20055791145152WayT.D.KaoM.C.LinJ.K.[PubMed]
  • 44. Menopause.201017510551063MafuvadzeB.BenakanakereI.HyderS.M.[PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.