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Biswas, P. Genistein for Breast Cancer. Encyclopedia. Available online: (accessed on 18 April 2024).
Biswas P. Genistein for Breast Cancer. Encyclopedia. Available at: Accessed April 18, 2024.
Biswas, Partha. "Genistein for Breast Cancer" Encyclopedia, (accessed April 18, 2024).
Biswas, P. (2022, March 03). Genistein for Breast Cancer. In Encyclopedia.
Biswas, Partha. "Genistein for Breast Cancer." Encyclopedia. Web. 03 March, 2022.
Genistein for Breast Cancer

Breast cancer (BC) is one of the most common malignancies in women. Genistein (GNT) is a soy-based phytoestrogen and is consumed regularly by Asian populations. This phytoestrogen may be one of the leading compounds as its safe and anticancer activities have already been tested in several in vitro and preclinical models. GNT has a structural similarity to 17 β-estradiol, and it binds to estrogen receptor ER-β with higher affinity compared to ER-α. Several studies suggested that GNT exerts pleiotropic effects, including inhibiting the cell cycle, inducing the cellular apoptosis process, suppressing metastasis and angiogenesis, modulating oxidative stress, and mammosphere formation in in vitro BC models. Furthermore, this phytoestrogen exerts several synergistic activities, as it can enhance the efficacy of conventional drugs against BC and reduce chemotherapeutic drug resistance. Moreover, many in vivo and clinical trials also support that GNT can be considered a promising chemopreventive agent for treating different types of BC.

genistein breast cancer molecular pharmacology

1. An Overview of Genistein (GNT)

Genistein (GNT) (IUPAC: 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one) is a phytoestrogen isoflavone that is widely available in soybean, mature seeds, and raw soy-related food (5.6–276 mg/100 g) [1] and legumes (0.2–0.6 mg/100 g) [2]. It possesses lower oral bioavailability, perhaps due to its high solubility in several polar solvents such as acetone, dimethylsulfoxide, and ethanol, and its poor solubility in water [3]. The oral administration of GNT results in high absorption with a tmax (transport maximum) of 5–6 h and t1/2 of 8 h [4][5]. GNT is rapidly distributed throughout the body by crossing the placental and blood–brain barriers. GNT is most abundant in the gastrointestinal tract and liver tissue distribution, consistent with its enterohepatic recycling [6]. GNT is absorbed rapidly and nearly completely in vivo. It showed high permeability in Caco-2 (3 × 10−5 cm/s) and Madin–Darby canine kidney (MDCKII) cells, where passive diffusion is the major transport mechanism, but breast cancer resistance protein (BCRP) may play a role in limiting its intestinal absorption [7][8][9]. In vivo, GNT undergoes a complex and extensive metabolic process that includes oxidation, reduction, conjugation, glucuronidation, sulfation, and limited CYP reaction [10][11][12][13][14][15]. Coldham et al. found that GNT has the highest concentrations in the gut (18.5 μg/g), followed by the liver (0.98 μg/g), plasma (0.79 μg/g), and reproductive tissues (uterus, ovary, vagina, and prostate, ranging from 0.12 to 0.28 μg/g) in rats [16]. The excretion of GNT depends on the activity of conjugating enzymes and relies on the efflux transporters’ capacity [17]. In vivo, ADME studies revealed that GNT metabolites are excreted via the intestinal, biliary, and renal tracts [18][19]. Although there is limited evidence that consuming large amounts of GNT in the diet causes a deleterious effect in humans, the toxicity of GNT on fertility and fetal development has been extensively studied in recent years. Several studies have demonstrated that therapeutically relevant doses of GNT have a harmful effect on BC differentiation, the estrous cycle, and fertility in rodent models [20][21]. This natural phytochemical can exhibit a wide range of important therapeutic activities, including antioxidant [22], anti-inflammatory [23], antibacterial [24], antiviral [25], antidiabetic [26], and anticancer activities [27]. GNT has proven its ability against various types of human cancers such as lung [28], liver [29], prostate [30], pancreatic [31], skin [32], cervical [33], uterine [34], colon [35], kidney [36], bladder [37], neuroblastoma [38], gastric [39], esophageal [40], pituitary [41], salivary gland [42], testicular [43], ovarian [44], and finally, breast cancer [45].

2. Cell-Specific Molecular Mechanisms of Genistein-Mediated Anti-Breast Cancer Activity In Vitro

Cancerous cell lines derived from humans are critical models for in vitro cancer research to determine the therapeutic advantage of anticancer agents [46]. Anticancer activity of phytochemicals is cell-specific, where one phytochemical is effective in one or more cell lines, and this may be the difference in the cell components system

2.1. The Effects of Genistein on MCF-7 BC Cells

According to Prietsch et al., GNT (0.01–100 µM) promoted apoptosis via mediating the autophagy-dependent mechanism and increasing the ratio of Bax/Bcl-2 and inhibiting the oxidative stress of cancer progression through changing the expression of antioxidant enzymes [47]. Liu et al. summarized that GNT (5–20 µM) induced apoptosis through the mitochondrial-dependent pathway by decreasing the Bcl-2/Bax ratio and increasing tumor suppressor gene p73 expression and ATM phosphorylation with G2/M phase arrest permanently [48]. Similarly, GNT (50–200 µM) halted cellular growth and induced apoptosis by following the downregulation of Bcl-2 protein, upregulation of Bax, and decreasing cyclin D1 expression in the MCF-7 BC cell line [49]. At a low concentration, GNT (1 µM) stimulates cell proliferation, but a higher concentration (25 µM) induces apoptosis pathways by upregulating the CDKN1A and p53 responsive genes and downregulating CCNG1 GADD45A, NF-κB, Bcl-2, TNFR, ESR1, NCOA2, and NCOA3 [50]. Another study investigated that GNT (50 µM) induced apoptosis by upregulating poly-(ADP-ribose)-polymerase and p53, and downregulating the Bcl-2/Bax protein ratio [51]. An in vitro study by Lemos investigated that GNT (10 µM) induced apoptosis by breaking the plasma membrane, nuclear membrane, and upregulating pS2 expression [52]. A later study reported that GNT (100 µM) mediated programmed cell death and suppressed cell growth by upregulating caspase 7, apoptosis signaling kinase-1, ADP ribose, and p38-dependent mitogen protein kinase [53]. Inhibition of metastasis and angiogenesis processes is a common mechanism in BC treatment. In vitro study demonstrated that GNT (3.125–12.5µM) decreased tumorigenic processes by increasing GSTP1 and RARβ2 gene expression and activity [54]. Shon et al. concluded that GNT suppressed angiogenesis by downregulating COX, TPA, and EROD proteins [55], while at 1–10 µg/mL, it inhibited angiogenesis by decreasing tyrosine kinase and ribosomal S6 kinases [56]. In an in vitro study, GNT lowered cell proliferation via mitochondrial-dependent pathways by reducing Fis1 (mitochondrial fission) and Opa1 (mitochondrial fusion) mRNA expression [57] at 10 nm–10 µM, while 4–10 mol/L of GNT inhibited cell proliferation by downregulating cyclin D1 and arresting the cell cycle in the G0/G1 phase, resulting in the blockage of cell survival, according to H. Jiang et al. [58].
Chen et al. reported that GNT (5–100 µM) inhibited the proliferation of cells by inducing apoptosis through IGF-1R-PI3 K/Akt-mediated pathway inactivation and upregulating the Bax/Bcl-2 ratio [59]. Furthermore, it has been shown that GNT (5–30 µM) inhibited BC cell growth, proliferation, and promoted apoptosis by following the downregulation of the Hedgehog–Gli1 signaling pathway and decreasing the mRNA level of Smo and Gli1 [60]. Marik et al. also found similar results, that GNT at a low concentration (0.1 µM) stimulates cancer progression, but GNT (20 µM) at a high concentration inhibits cell proliferation by downregulating mRNA expression of ER-α protein and arresting the cell cycle at the G2/M phase [61]. Furthermore, Chinni et al. reported that GNT (100 µM) inhibits cell proliferation by downregulating Akt-mediated signaling pathways, decreasing telomere length, and overexpression of cyclin-dependent kinase inhibitor p21WAF1 [62]. An early study demonstrated that GNT (50 µM) inhibited tumor growth with apoptosis inductions by increasing Ca2+-dependent pro-apoptotic protease, mµ-calpain, and caspase-12 [63]. On the other hand, Liao et al. showed that GNT (100 µM) inhibited cell growth alongside decreasing paclitaxel-induced tubulin polymerization, Bcl-2, cyclin B1, and CDK2 kinase, leading to cell cycle arrest at the G2/M phase [64]. Chen et al. showed that GNT (50–100 µM) suppressed cell division through uplifting heat shock protein (HSP) activity and reducing SRF mRNA, RAG-1, and DOC 2 expression [65]. GNT (40 nm–2 µM) inhibits mammosphere formation in BC stem cells by suppressing PI3K/Akt signaling through upregulating the PTEN expression [66]. A similar result found by Y. Liu et al. confirmed that GNT (40 nm–2 µM) inhibited mammosphere formation and induced stem cell differentiation by activating PI3K/Akt and MEK/ERK signaling in a paracrine manner, increasing E-cadherin mRNA expression by reducing the ratio of CD44+/CD24-/ESA in MCF-7 BC cells [67]. GNT (1 µM) induces an anticancer effect through upregulating pro-inflammatory genes, i.e., pS2 and COX2, and downregulating anti-inflammatory gene expression, i.e., TFGβ and PPARγ in MCF-7 BC cells [68]. Furthermore, Kazi et al. reported that GNT (50–200 µM) halts cancer progression by upregulating IκB-α and p27 (Kip1) levels, and downregulating proteasomal chymotrypsin-like activity and CDKs [69]. Epigenetics regulation by GNT (60–100 µM) is mediated by diminishing DNA methylation levels, DNMT1 expression, and DNA methyltransferase enzyme activity. However, this reduction in DNA methylation occurs in the promoter region of multiple tumor suppressor genes (TSGs) such as adenomatous polyposis coil (APC), ataxia telangiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), and mammary serpin peptidase inhibitor (SERPINB5) [70].

2.2. The Effects of Genistein on MDA-MB-231 BC Cells

Recently, an experiment conducted by Liu et al. GNT (5–20 µM) induced apoptosis through the mitochondrial-dependent pathway by reducing the Bcl-2/Bax ratio and inhibiting cell growth and increasing the expression of p73, leading to the activation of G2/M phase arrest and the ATM/Cdc25C/Chk2/Cdc2 checkpoint pathway [48]. GNT prompted the apoptotic pathway and directly inhibited the growth of cells through the prevention of NF-κB signaling by the Notch-1 pathway and by downregulating cyclin B1 and Bcl-2 expression, resulting in the arrest of the cell cycle at the G2/M phase at 5–20 µM [71], while at 5–50 µM, this phytochemical induced apoptosis by targeting the endogenous copper ion, reducing Cu(II) to Cu(I) through the production of reactive oxygen species (ROS) [72]. Before that, an in vitro study by Dampier et al. reported that GNT (10 µM) induced apoptosis and inhibited cell proliferation and cell cycle arrest at the G2 phase, degrading proto-oncogene c-Fos and prohibiting protein-1 (AP-1), and also ERK activity [73]. Another study by Yang et al. demonstrated that GNT (50 µM) exerted apoptosis by upregulating poly-(ADP-ribose)-polymerase, activating p53, and downregulating Bcl-2/Bax protein [51].
In the case of angiogenesis, Mukund et al. explained that GNT (100 µM) reduced angiogenesis by blocking the transactivation of downstream HIF-1α effectors, e.g., VEGF, leading to the reduction in hypoxia-inducible factor-1α expression in MDA-MB-231 BC cells [74]. Furthermore, 1–10 µg/mL of GNT suppressed angiogenesis and cell mutation by decreasing tyrosine kinase, ribosomal S6 kinases, and DNA topoisomerases I and II [56], while at a 50 µM concentration, it decreased angiogenesis and inhibited cell division through the underlying mechanism of downregulating COX, topoisomerase II enzyme TPA, and EROD protein activity [55]. Followed by angiogenesis, GNT (15–30 µM) [75] and (5–20 µM) [76] obstructed cancer cell migration and invasion, respectively, by lowering levels of CDKs, tyrosine kinase, and paracrine stimulation and decreasing MEK5, ERK5, phospho-ERK5, NF-κB/p65, and Bcl-2/Bax.
Another study conducted by Kousidou et al. reported that GNT (35–100 µM) progresses slowdown invasiveness by decreasing MMP gene expression, PTK activity, and glucose uptake rate, leading to phagocytosis of cancerous cells [77]. Apart from this, it reduces cell viability by decreasing the DNA methyltransferase activity and DNMT1 expression and affecting the expression of TSGs, i.e., APC, ATM, PTEN, and SERPINB5 at 60–100 µM of GNT [70]. Another recent study by Pons et al. summarized that GNT (1 µM) causes a considerable decrease in cell viability through the mitogen-dependent protein kinase pathway and by promoting apoptosis mechanisms [68].
In MDA-MB-231 BC cells, cell growth control is a significant target for GNT. Gong et al. stated that GNT (5–50 µM) inhibited cell growth by partly inducing apoptosis via downregulation of the Akt and NF-κB cascade pathways [78]. In another in vitro analysis, the cell growth inhibitory activity was evidenced by GNT (2.5–400 µM) through the upregulation of two crucial TSGs, p21WAF1 (p21) and p16INK4a (p16), and the downregulation of two tumor-promoting genes, c-MYC and BMI1, ultimately inhibiting cancer progression [79]. Y. Fang et al. concluded that GNT (40 µM) inhibited cellular growth by following the activation of DNA-dependent damage response and the ATR signaling pathway and activating the BRCA-1 complex, inhibiting the cohesion complex, and increasing phosphatide, which is distributed among CDK1, CDK2, and CDK3 [80]. Recently, it was established that GNT (1000 ppm) suppressed tumor growth by cell cycle regulation via maintaining the expression level of the cyclin D1 protein, leading to G0/G1 phase arrest, which causes cell cycle blockage [58]. Subsequently, Rajah et al. summarized that GNT (10–100 µM) inhibited tumor growth by downregulating MEK5, pERK5, and NF-κB proteins [81]. In the case of cell proliferation, a low dose of GNT (10 µM) slightly inhibited cell proliferation by reducing the P-STAT3/STAT-5 ratio [57]. In comparison, at a double dose, i.e., 20–40 µM, it significantly prevented cell proliferation by inducing apoptosis and suppressing Skp2 expression by upregulating the tumor suppressor genes, i.e., p21 and p27, resulting in G2/M phase arrest [82]. Li et al. investigated that GNT (5–20 µM) inhibited cell differentiation with cell cycle arrest at the G2/M phase by decreasing CDK1, cyclin B1, Cdc25C, c-Jun, and c-Fos levels [83]. GNT can also play a role in MDA-MB-231 by inhibiting mammosphere formation. A lower dose of GNT (2 µM) prevents mammosphere formation through PI3K/Akt signaling by increasing the PTEN expression [66], while at a higher dose, GNT (40 nm–2 µM) prevents the formation of mammosphere cells and promotes differentiation through the PI3K/Akt and MEK/ERK signaling pathway by reducing the CD44+/CD24-/ESA ratio and increasing E-cadherin mRNA expression [67]. Finally, GNT (50 µM) impedes primary tumor formation by downregulating chelator neocuproine and Bcl-2/Bax and by upregulating the caspase-3 pathway [72].

2.3. The Effects of Genistein on T-47D Breast Cancer Cells

Mukund et al. summarize that GNT (50 µM) lowered angiogenesis by preventing the transactivation of downstream HIF-1α effectors such as VEGF, reducing the expression of hypoxia-inducible factor-1α in the T-47D BC cell line [74]. Cell proliferation efficacy was evident by GNT (10 nm) with apoptosis induction through the mitochondrial-dependent pathway via upregulating the cyt-C and oxidase activity, and downregulating the ATP synthase/cytochrome c oxidase ratio [57]. GNT at 1 nm–100 µM inhibits cell proliferation through ERK1/2-mediated signaling by the downregulation of phosphorylated p90RSK [84], while 10 µM of GNT induces apoptosis and inhibits cell proliferation through degrading proto-oncogene c-Fos levels and prohibiting protein 1 (AP-1) and ERK expression [73]. Another in vitro study by Rajah revealed that GNT (10–100 µM) inhibits cell proliferation and tumor growth by downregulating MEK5, pERK5, and NF-κB proteins [81]. Additionally, a high GNT (20 M) concentration inhibits cell proliferation by reducing ER-messenger RNA transcription and arresting the cell cycle at the G2/M phase [61]. According to Sotoca et al., GNT (500 nm) inhibited cell growth and induced apoptosis by activating cytoskeleton restructuring that results in interaction among integrins, focalized adhesion kinase, and CDC42 that leads to cell cycle arrest in the T-47D BC cell line [85], while according to Pons et al., GNT (1 µM) caused a significant decrease in cell viability by increasing Sirt1, TGFβ, and PRARγ and decreasing IL-1β expression in T-47D BC cells [68].

2.4. The Effects of Genistein on HCC1395 Breast Cancer Cells

Lee et al. demonstrated that GNT (1–200 µM) inhibited HCC1395 cell invasion and metastasis through the upregulation of TFPI-2, ATF3, DNMT1, and MTCBP-1 gene expression and the downregulation of MMP-2, MMP-7, CXCL12 genes, leading to cell cycle arrest at the G2/M phase, therefore reducing cell viability [86].

2.5. The Effects of Genistein on HCC38 Breast Cancer Cells

Donovan stated that GNT (4–10 ppm) inhibited cell growth by increasing the BRCA1 protein level and reducing CpG methylation, consequently decreasing the aryl hydrocarbon receptor (AhR) binding at BRCA1 in the HCC38 cell line [87].

2.6. The Effects of Genistein on Hs578t Breast Cancer Cells

According to Parra et al., GNT (1–50 µM) inhibits cell viability and induces apoptosis through the downregulation of mir-155, resulting in the upregulation of casein kinase, FOXO3a, p27, and PTEN expression, and the reduction of β-catenin in the Hs578t cell line [88].

2.7. The Effects of Genistein on DD-762 and Sm-MTC Breast Cancer Cells

Nakagawa et al. appraised that GNT (7–274.2 µM) inhibited cell proliferation by upregulating caspase-3 protein activity in DD-762 and Sm-MTC BC cell lines [89].

2.8. The Effects of Genistein on BT-474 Breast Cancer Cells

GNT at a low concentration (1 µM) could promote cancer but at a high concentration (50 µM), it inhibits cell division by downregulating tyrosine kinase, HER2 activation, and the MAPK pathway [90]. GNT (3.125–25 M) inhibits cell replication and arrests the cell cycle in the G2/M phase, and inhibits the expression of EGFR, HER2, and ER-alpha [91].

2.9. The Effects of Genistein on BT20 Breast Cancer Cells

Cappelletti et al. revealed that GNT (15–30 µM) inhibits metastasis by lowering levels of CDKs, tyrosine kinase, DNA topoisomerase II, and paracrine stimulation in the BT20 cell line [75].

2.10. The Effects of Genistein on 21PT Breast Cancer Cells

Marik et al. demonstrated that GNT at a 0.1 M concentration stimulated cancer progression, while 20 M of GNT inhibited cell proliferation by decreasing ER-messenger RNA expression and arresting the cell cycle at the G2/M phase in the 21PT cell line [61].

2.11. The Effects of Genistein on 184-B5/HER Breast Cancer Cells

Katdare et al. showed that GNT (2.5–10 µM) impeded the cell cycle and induced apoptosis by increasing the P16INK4a gene and decreasing HER-2/neu and tyrosine kinase [92].

2.12. The Effects of Genistein on MCF-10A, MCF-ANeoT, and MCF-T63B Breast Cancer Cells

An early study showed that GNT (1–10 µg/mL) obstructed angiogenesis and cell mutation by decreasing the expression of ribosomal S6 kinases and tyrosine kinase [56].

3. Clinical Trials

Human clinical trials have confirmed the in vitro research findings. In some cases, when consumed at a consistent dose, pure GNT had no estrogenic effect on breast tissue [93][94], although in other cases, dietary soy supplementation had pro-estrogenic effects on breast tissue [95][96][97]. Several secondary endpoints were evaluated in a recently published clinical study to determine whether purified GNT affects endometrial thickness, vaginal cytology, and breast density [93][54][55]. Following the implementation of safety measures, it was possible to identify the potential estrogenic effects of 54 mg/day of purified GNT as indicators of BC risk in the research participants. Indeed, while the placebo group maintained a constant endometrial thickness, the GNT group demonstrated a time-dependent reduction that reached statistical significance during the 36-month follow-up (approximately 12% reduction, p < 0.01). Moreover, levels of gene expression of BRCA-1 and 2 breast tumor suppressor genes [98][99] have been preserved for three years in the GNT-administered group, while levels of both BRCA-1 and 2 have decreased in the placebo group [93][94]. GNT also significantly reduced sister chromatid exchanges, implying that it may prevent genotoxicity and subsequent mutagenesis [94]. In this regard, based on the use of GNT in BC, two clinical trials—a phase II study entitled “Gemcitabine Hydrochloride and GNT in Treating Women with Stage IV BC” (NCT00244933) and a phase I study entitled “GNT in Preventing Breast or Endometrial Cancer in Healthy Postmenopausal Women” (NCT00099008)—have been completed, but the results are not yet published.

4. Nano-Formulation of Genistein for Breast Cancer Treatment

GNT research for cancer treatment has been extended in recent years due to evidence of lower disease risk associated with its administration and a quest for pharmacological medicines that impact growth factor signaling pathways in cells. A significant drawback of GNT as a natural substance is its low water solubility. This may necessitate modifying its chemical structure to increase solubility and boost bioavailability [100].
However, the advancement of nanomedicines has the potential to overcome phytochemical limitations and allied health concerns, such as improved solubility, increased bioavailability, targeted treatment of tumor cells or tissues while avoiding healthy cell damage, and increased cell take-up. Nanomedicines could provide new avenues for circumventing these concerns. Additional advantages may include improved blood stability, multifunctional nanomedicine design, minimal interaction with synthetic medications, and improved anticancer activity [101]. Furthermore, multidrug resistance (MDR) is one of the most important variables contributing to the failure of phytochemical therapy in cancer. MDR can be circumvented using a new technique including nanocarriers and phytochemical delivery. Modifying the biophysical interaction between the nanomedicines and cancer cell membrane lipids can increase phytochemical delivery and overcome drug resistance. This is accomplished by improving the transport of phytochemicals to target tissues through surface modification of nanomedicines [102][103]. Currently, advancements in treatment efficiency through nanomedicines have received much attention because of the increased delivery of phytochemicals to tumors and cancer cells. Numerous highly successful nanomedicines have been employed to enhance phytochemicals’ physicochemical qualities and anticancer activity [104]. BC treatment with doxorubicin and GNT is improved by using multifunctional hybrid nano-constructs that enable intracellular localization of the drugs [105]. A research study by Jimmy Pham and his colleagues demonstrated that mitochondriotropic nano-emulsified genistein-loaded vehicles showed more effective potential against hepatic and colon carcinomas than the control drugs [106].In one study, cervical cancers were treated with bioflavonoid genistein-loaded chitosan nanoparticles targeted to the folate receptor, which had a significant anticancer effect. The naturally derived chitosan nanoparticles exhibited potent biodegradability and biocompatibility when coated with the GNT [107]. Additionally, genistein-loaded biodegradable TPGS-b-PCL nanoparticles possessed enhanced therapeutic effects in cervical cancer cells [108]. Moreover, the nanoformulation of GNT promoted selective apoptosis in the cell line of oral squamous cancer by suppressing the expression of a 3PK-EZH2 signaling pathway [109].


  1. Motlekar, N.; Khan, M.A.; Youan, B.B.C. Preparation and characterization of genistein containing poly(ethylene glycol) microparticles. J. Appl. Polym. Sci. 2006, 101, 2070–2078.
  2. Setchell, K.D.; Faughnan, M.S.; Avades, T.; Zimmer-Nechemias, L.; Brown, N.M.; Wolfe, B.E.; Brashear, W.T.; Desai, P.; Oldfield, M.F.; Botting, N.P.; et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am. J. Clin. Nutr. 2003, 77, 411–419.
  3. Chandrasekharan, A.A.; Aglin, S.C.A.A. Pharmacokinetics of Dietary Isoflavones. J. Steroids Horm. Sci. 2013, S12, 4.
  4. Jaiswal, N.; Akhtar, J.; Singh, S.P.; Ahsan, F. An Overview on Genistein and its Various Formulations. Drug Res. 2019, 69, 305–313.
  5. Liu, Y.; Hu, M. Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perfused rat intestinal model. Drug Metab. Dispos. 2002, 30, 370–377.
  6. Enokizono, J.; Kusuhara, H.; Sugiyama, Y. Effect of breast cancer resistance protein (Bcrp/Abcg2) on the disposition of phytoestrogens. Mol. Pharmacol. 2007, 72, 967–975.
  7. Álvarez, A.I.; Vallejo, F.; Barrera, B.; Merino, G.; Prieto, J.G.; Tomas-Barberan, F.; Espín, J.C. Bioavailability of the glucuronide and sulfate conjugates of genistein and daidzein in breast cancer resistance protein 1 knockout mice. Drug Metab. Dispos. 2011, 39, 2008–2012.
  8. Chang, Y.C.; Nair, M.G. Metabolism of daidzein and genistein by intestinal bacteria. J. Nat. Prod. 1995, 58, 1892–1896.
  9. Kulling, S.E.; Honig, D.M.; Metzler, M. Oxidative metabolism of the soy isoflavones daidzein and genistein in humans in vitro and in vivo. J. Agric. Food Chem. 2001, 49, 3024–3033.
  10. Heinonen, S.M.; Hoikkala, A.; Wähälä, K.; Adlercreutz, H. Metabolism of the soy isoflavones daidzein, genistein and glycitein in human subjects. Identification of new metabolites having an intact isoflavonoid skeleton. J. Steroid Biochem. Mol. Biol. 2003, 87, 285–299.
  11. Yang, Z.; Zhu, W.; Gao, S.; Xu, H.; Wu, B.; Kulkarni, K.; Singh, R.; Tang, L.; Hu, M. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS/MS method: Application to an oral bioavailability study of genistein in mice. J. Pharm. Biomed. Anal. 2010, 53, 81–89.
  12. Shelnutt, S.R.; Cimino, C.O.; Wiggins, P.A.; Ronis, M.J.J.; Badger, T.M. Pharmacokinetics of the glucuronide and sulfate conjugates of genistein and daidzein in men and women after consumption of a soy beverage. Am. J. Clin. Nutr. 2002, 76, 588–594.
  13. Hosoda, K.; Furuta, T.; Yokokawa, A.; Ogura, K.; Hiratsuka, A.; Ishii, K. Plasma profiling of intact isoflavone metabolites by high-performance liquid chromatography and mass spectrometric identification of flavone glycosides daidzin and genistin in human plasma after administration of kinako. Drug Metab. Dispos. 2008, 36, 1485–1495.
  14. Coldham, N.G.; Sauer, M.J. Pharmacokinetics of genistein in the rat: Gender-related differences, potential mechanisms of biological action, and implications for human health. Toxicol. Appl. Pharmacol. 2000, 164, 206–215.
  15. Hu, M.; Chen, J.; Lin, H. Metabolism of flavonoids via enteric recycling: Mechanistic studies of disposition of apigenin in the Caco-2 cell culture model. J. Pharmacol. Exp. Ther. 2003, 307, 314–321.
  16. Zhou, S.; Hu, Y.; Zhang, B.-L.; Teng, Z.; Gan, H.; Yang, Z.; Wang, Q.; Huan, M.; Mei, Q. Dose-dependent absorption, metabolism, and excretion of genistein in rats. J. Agric. Food Chem. 2008, 56, 8354–8359.
  17. Wang, S.W.J.; Chen, J.; Jia, X.; Tam, V.H.; Hu, M. Disposition of flavonoids via enteric recycling: Structural effects and lack of correlations between in vitro and in situ metabolic properties. Drug Metab. Dispos. 2006, 34, 1837–1848.
  18. Jefferson, W.N.; Williams, C.J. Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. Reprod. Toxicol. 2011, 31, 272–279.
  19. Spagnuolo, C.; Russo, G.L.; Orhan, I.E.; Habtemariam, S.; Daglia, M.; Sureda, A.; Nabavi, S.F.; Devi, K.P.; Loizzo, M.R.; Tundis, R.; et al. Genistein and cancer: Current status, challenges, and future directions. Adv. Nutr. 2015, 6, 408–419.
  20. Park, C.E.; Yun, H.; Lee, E.-B.; Min, B.-I.; Bae, H.; Choe, W.; Kang, I.; Kim, S.-S.; Ha, J. The antioxidant effects of genistein are associated with AMP-activated protein kinase activation and PTEN induction in prostate cancer cells. J. Med. Food 2010, 13, 815–820.
  21. Ji, G.; Yang, Q.; Hao, J.; Guo, L.; Chen, X.; Hu, J.; Leng, L.; Jiang, Z. Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms. Int. Immunopharmacol. 2011, 11, 762–768.
  22. Hong, H.; Landauer, M.R.; Foriska, M.A.; Ledney, G.D. Antibacterial activity of the soy isoflavone genistein. J. Basic Microbiol. 2006, 46, 329–335.
  23. Lecher, J.C.; Diep, N.; Krug, P.W.; Hilliard, J.K. Genistein has antiviral activity against herpes b virus and acts synergistically with antiviral treatments to reduce effective dose. Viruses 2019, 11, 499.
  24. Gilbert, E.R.; Liu, D. Anti-diabetic functions of soy isoflavone genistein: Mechanisms underlying its effects on pancreatic β-cell function. Food Funct. 2013, 4, 200–212.
  25. Tuli, H.S.; Tuorkey, M.J.; Thakral, F.; Sak, K.; Kumar, M.; Sharma, A.K.; Sharma, U.; Jain, A.; Aggarwal, V.; Bishayee, A. Molecular mechanisms of action of genistein in cancer: Recent advances. Front. Pharmacol. 2019, 10, 1336.
  26. Wu, T.C.; Lin, Y.C.; Chen, H.L.; Huang, P.R.; Liu, S.Y.; Yeh, S.L. The enhancing effect of genistein on apoptosis induced by trichostatin A in lung cancer cells with wild type p53 genes is associated with upregulation of histone acetyltransferase. Toxicol. Appl. Pharmacol. 2016, 292, 94–102.
  27. Der Wang, S.; Chen, B.C.; Kao, S.T.; Liu, C.J.; Yeh, C.C. Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. BMC Complement. Altern. Med. 2014, 14, 26.
  28. Chiyomaru, T.; Yamamura, S.; Fukuhara, S.; Yoshino, H.; Kinoshita, T.; Majid, S.; Saini, S.; Chang, I.; Tanaka, Y.; Enokida, H.; et al. Genistein Inhibits Prostate Cancer Cell Growth by Targeting miR-34a and Oncogenic HOTAIR. PLoS ONE 2013, 8, e70372.
  29. Luo, Y.; Wang, S.-X.; Zhou, Z.-Q.; Wang, Z.; Zhang, Y.-G.; Zhang, Y.; Zhao, P. Apoptotic effect of genistein on human colon cancer cells via inhibiting the nuclear factor-kappa B (NF-κB) pathway. Tumor Biol. 2014, 35, 11483–11488.
  30. Danciu, C.; Borcan, F.; Bojin, F.; Zupko, I.; Dehelean, C. Effect of the isoflavone genistein on tumor size, metastasis potential and melanization in a B16 mouse model of murine melanoma. Nat. Prod. Commun. 2013, 8, 1934578X1300800318.
  31. Kim, S.H.; Kim, S.H.; Kim, Y.B.; Jeon, Y.T.; Lee, S.C.; Song, Y.S. Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells. Ann. N. Y. Acad. Sci. 2009, 1171, 495–500.
  32. Buathong, N.; Poonyachoti, S.; Deachapunya, C. Isoflavone genistein modulates the protein expression of toll-like receptors in cancerous human endometrial cells. J. Med. Assoc. Thail. 2015, 98, S31-8.
  33. Zhang, Z.; Wang, C.-Z.; Du, G.-J.; Qi, L.-W.; Calway, T.; He, T.-C.; Du, W.; Yuan, C.-S. Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int. J. Oncol. 2013, 43, 289–296.
  34. Qi, W.; Weber, C.R.; Wasland, K.; Savkovic, S.D. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer 2011, 11, 219.
  35. Hirata, H.; Hinoda, Y.; Shahryari, V.; Deng, G.; Tanaka, Y.; Tabatabai, Z.L.; Dahiya, R. Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells. Br. J. Cancer 2014, 110, 1645–1654.
  36. Choudhury, S.R.; Karmakar, S.; Banik, N.L.; Ray, S.K. Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplifi. Investig. New Drugs 2010, 28, 812–824.
  37. Yu, D.; Shin, H.S.; Lee, Y.S.; Lee, D.; Kim, S.; Lee, Y.C. Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1. Oncol. Rep. 2014, 31, 673–678.
  38. Tang, L.; Lee, A.H.; Xu, F.; Zhang, T.; Lei, J.; Binns, C.W. Soya and isoflavone intakes associated with reduced risk of oesophageal cancer in north-west China. Public Health Nutr. 2015, 18, 130–134.
  39. Zhao, Q.X.; Zhao, M.; Parris, A.B.; Xing, Y.; Yang, X. Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells. Int. J. Oncol. 2016, 49, 1203–1210.
  40. Ma, J.; Zong, Z.H.; Wang, Z.Y.; Zhong, M. Effects of Genistein on the proliferation and expression of survivin in salivary adenoid cystic carcinoma cell line SACC-83. Hua Xi Kou Qiang Yi Xue Za Zhi 2007, 25, 97–99.
  41. Song, M.; Tian, X.; Lu, M.; Zhang, X.; Ma, K.; Lv, Z.; Wang, Z.; Hu, Y.; Xun, C.; Zhang, Z.; et al. Genistein exerts growth inhibition on human osteosarcoma MG-63 cells via PPARγ pathway. Int. J. Oncol. 2015, 46, 1131–1140.
  42. Ning, Y.X.; Li, Q.X.; Ren, K.Q.; Quan, M.F.; Cao, J.G. 7-difluoromethoxyl-5,4′-di-n-octyl genistein inhibits ovarian cancer stem cell characteristics through the downregulation of FOXM1. Oncol. Lett. 2014, 8, 295–300.
  43. Marik, R.; Allu, M.; Anchoori, R.; Stearns, V.; Umbricht, C.B.; Khan, S. Potent genistein derivatives as inhibitors of estrogen receptor alpha-positive breast cancer. Cancer Biol. Ther. 2011, 11, 883–892.
  44. Wang, T.T.Y.; Sathyamoorthy, N.; Phang, J.M. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996, 17, 271–275.
  45. Naik, A.V.; Sellappan, K. Assessment of Genotoxic potential of Annonacin and Annona muricata L. extracts on human breast cancer (MCF-7) cells. Adv. Tradit. Med. 2021, 21, 779–789.
  46. Liu, X.; Sun, C.; Jin, X.; Li, P.; Ye, F.; Zhao, T.; Gong, L.; Li, Q. Genistein enhances the radiosensitivity of breast cancer cells via G2/M cell cycle arrest and apoptosis. Molecules 2013, 18, 13200–13217.
  47. Lavigne, J.A.; Takahashi, Y.; Chandramouli, G.V.R.; Liu, H.; Perkins, S.N.; Hursting, S.D.; Wang, T.T.Y. Concentration-dependent effects of genistein on global gene expression in MCF-7 breast cancer cells: An oligo microarray study. Breast Cancer Res. Treat. 2008, 110, 85–98.
  48. Yang, X.; Taylor, L.; Yu, J.; Fenton, M.J.; Polgar, P. Different effects of genistein on molecular markers related to apoptosis in two phenotypically dissimilar breast cancer cell lines. J. Cell. Biochem. 2001, 82, 78–88.
  49. Jiang, H.; Fan, J.; Cheng, L.; Hu, P.; Liu, R. The anticancer activity of genistein is increased in estrogen receptor beta 1-positive breast cancer cells. Onco. Targets. Ther. 2018, 11, 8153–8163.
  50. De Lemos, M.L. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann. Pharmacother. 2001, 35, 1118–1121.
  51. Shim, H.Y.; Park, J.H.; Paik, H.D.; Nah, S.Y.; Kim, D.S.H.L.; Han, Y.S. Genistein-induced apoptosis of human breast cancer MCF-7 cells involves calpain-caspase and apoptosis signaling kinase 1-p38 mitogen-activated protein kinase activation cascades. Anticancer Drugs 2007, 18, 649–657.
  52. King-Batoon, A.; Leszczynska, J.M.; Klein, C.B. Modulation of gene methylation by genistein or lycopene in breast cancer cells. Environ. Mol. Mutagen. 2008, 49, 36–45.
  53. Shon, Y.H.; Park, S.D.; Nam, K.S. Effective chemopreventive activity of genistein against human breast cancer cells. J. Biochem. Mol. Biol. 2006, 39, 448–451.
  54. Tanos, V.; Brzezinski, A.; Drize, O.; Strauss, N.; Peretz, T. Synergistic inhibitory effects of genistein and tamoxifen on human dysplastic and malignant epithelial breast cells in vitro. Eur. J. Obstet. Gynecol. Reprod. Biol. 2002, 102, 188–194.
  55. Pons, D.G.; Nadal-Serrano, M.; Blanquer-Rossello, M.M.; Sastre-Serra, J.; Oliver, J.; Roca, P. Genistein modulates proliferation and mitochondrial functionality in breast cancer cells depending on ERalpha/ERbeta ratio. J. Cell. Biochem. 2014, 115, 949–958.
  56. Chen, J.; Duan, Y.; Zhang, X.; Ye, Y.; Ge, B.; Chen, J. Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells. Food Funct. 2015, 6, 995–1000.
  57. Fan, P.; Fan, S.; Wang, H.; Mao, J.; Shi, Y.; Ibrahim, M.M.; Ma, W.; Yu, X.; Hou, Z.; Wang, B.; et al. Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res. Ther. 2013, 4, 146.
  58. Wei, W.; Chen, Z.-J.; Zhang, K.-S.; Yang, X.; Wu, Y.-M.; Chen, X.-H.; Huang, H.-B.; Liu, H.-L.; Cai, S.-H.; Du, J.; et al. The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptornegative breast cancer cells in vitro and in vivo. Cell Death Dis. 2014, 5, e1428.
  59. Chinni, S.R.; Alhasan, S.A.; Multani, A.S.; Pathak, S.; Sarkar, F.H. Pleotropic effects of genistein on MCF-7 breast cancer cells. Int. J. Mol. Med. 2003, 12, 29–34.
  60. Sergeev, I.N. Genistein induces Ca 2+-mediated, calpain/caspase-12-dependent apoptosis in breast cancer cells. Biochem. Biophys. Res. Commun. 2004, 321, 462–467.
  61. Paterni, I.; Granchi, C.; Katzenellenbogen, J.A.; Minutolo, F. Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids 2014, 90, 13–29.
  62. Liao, C.H.; Pan, S.L.; Guh, J.H.; Teng, C.M. Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells. Biochem. Pharmacol. 2004, 67, 2031–2038.
  63. Chen, W.F.; Huang, M.H.; Tzang, C.H.; Yang, M.; Wong, M.S. Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochim. Biophys. Acta—Mol. Basis Dis. 2003, 1638, 187–196.
  64. Liu, Y.; Zou, T.; Wang, S.; Chen, H.; Su, D.; Fu, X.; Zhang, Q.; Kang, X. Genistein-induced differentiation of breast cancer stem/progenitor cells through a paracrine mechanism. Int. J. Oncol. 2016, 48, 1063–1072.
  65. Pons, D.G.; Vilanova-Llompart, J.; Gaya-Bover, A.; Alorda-Clara, M.; Oliver, J.; Roca, P.; Sastre-Serra, J. The phytoestrogen genistein affects inflammatory-related genes expression depending on the ERα/ERβ ratio in breast cancer cells. Int. J. Food Sci. Nutr. 2019, 70, 941–949.
  66. Hwang, J.T.; Lee, Y.K.; Shin, J.I.; Park, O.J. AnTi-inflammatory and anticarcinogenic effect of genistein alone or in combination with capsaicin in TPA-treated rat mammary glands or mammary cancer cell line. Ann. N. Y. Acad. Sci. 2009, 1171, 415–420.
  67. Kazi, A.; Daniel, K.G.; Smith, D.M.; Kumar, N.B.; Dou, Q.P. Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem. Pharmacol. 2003, 66, 965–976.
  68. Xie, Q.; Bai, Q.; Zou, L.-Y.; Zhang, Q.-Y.; Zhou, Y.; Chang, H.; Yi, L.; Zhu, J.-D.; Mi, M.-T. Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells. Genes Chromosom. Cancer 2014, 53, 422–431.
  69. 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, 337–343.
  70. Ullah, M.F.; Ahmad, A.; Zubair, H.; Khan, H.Y.; Wang, Z.; Sarkar, F.H.; Hadi, S.M. Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species. Mol. Nutr. Food Res. 2011, 55, 553–559.
  71. Dampier, K.; Hudson, E.A.; Howells, L.M.; Manson, M.M.; Walker, R.A.; Gescher, A. Differences between human breast cell lines in susceptibility towards growth inhibition by genistein. Br. J. Cancer 2001, 85, 618–624.
  72. Cappelletti, V.; Fioravanti, L.; Miodini, P.; di Fronzo, G. Genistein blocks breast cancer cells in the G2M phase of the cell cycle. J. Cell. Biochem. 2000, 79, 594–600.
  73. Kousidou, O.C.; Mitropoulou, T.N.; Roussidis, A.E.; Kletsas, D.; Theocharis, A.D.; Karamanos, N.K. Genistein suppresses the invasive potential of human breast cancer cells through transcriptional regulation of metalloproteinases and their tissue inhibitors. Int. J. Oncol. 2005, 26, 1101–1109.
  74. Montales, M.T.E.; Rahal, O.M.; Kang, J.; Rogers, T.J.; Prior, R.L.; Wu, X.; Simmen, R.C. Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis 2012, 33, 652–660.
  75. Gong, L.; Li, Y.; Nedeljkovic-Kurepa, A.; Sarkar, F.H. Inactivation of NF-κB by genistein is mediated via Akt signaling pathway in breast cancer cells. Oncogene 2003, 22, 4702–4709.
  76. Mukund, V.; Saddala, M.S.; Farran, B.; Mannavarapu, M.; Alam, A.; Nagaraju, G.P. Molecular docking studies of angiogenesis target protein HIF-1α and genistein in breast cancer. Gene 2019, 701, 169–172.
  77. Li, Y.; Chen, H.; Hardy, T.M.; Tollefsbol, T.O. Epigenetic Regulation of Multiple Tumor-Related Genes Leads to Suppression of Breast Tumorigenesis by Dietary Genistein. PLoS ONE 2013, 8, e54369.
  78. Fang, Y.; Zhang, Q.; Wang, X.; Yang, X.; Wang, X.; Huang, Z.; Jiao, Y.; Wang, J. Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells. Int. J. Oncol. 2016, 48, 1016–1028.
  79. Rajah, T.T.; Du, N.; Drews, N.; Cohn, R. Genistein in the presence of 17β-estradiol inhibits proliferation of ERβ breast cancer cells. Pharmacology 2009, 84, 68–73.
  80. Ye, D.; Li, Z.; Wei, C. Genistein inhibits the S-phase kinase-associated protein 2 expression in breast cancer cells. Exp. Ther. Med. 2018, 15, 1069–1075.
  81. Gwin, J.; Drews, N.; Ali, S.; Stamschror, J.; Sorenson, M.; Rajah, T.T. Effect of genistein on p90RSK phosphorylation and cell proliferation in T47D breast cancer cells. Anticancer Res. 2011, 31, 209–214.
  82. Sotoca, A.M.; Gelpke, M.D.S.; Boeren, S.; Ström, A.; Gustafsson, J.; Murk, A.J.; Rietjens, I.; Vervoort, J. Quantitative Proteomics and Transcriptomics Addressing the Estrogen Receptor Subtype-mediated Effects in T47D Breast Cancer Cells Exposed to the Phytoestrogen Genistein. Mol. Cell. Proteom. 2011, 10, M110.002170.
  83. Li, Z.; Li, J.; Mo, B.; Hu, C.; Liu, H.; Qi, H.; Wang, X.; Xu, J. Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol. Vitr. 2008, 22, 1749–1753.
  84. Donovan, M.G.; Selmin, O.I.; Doetschman, T.C.; Romagnolo, D.F. Epigenetic activation of BRCA1 by genistein in vivo and triple negative breast cancer cells linked to antagonism toward aryl hydrocarbon receptor. Nutrients 2019, 11, 2559.
  85. De La Parra, C.; Castillo-Pichardo, L.; Cruz-Collazo, A.; Cubano, L.; Redis, R.; Calin, G.; Dharmawardhane, S. Soy isoflavone genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein. Nutr. Cancer 2016, 68, 154–164.
  86. Nadal-Serrano, M.; Pons, D.G.; Sastre-Serra, J.; Blanquer-Rossellò, M.M.; Roca, P.; Oliver, J. Genistein modulates oxidative stress in breast cancer cell lines according to ERa/ERβ ratio: Effects on mitochondrial functionality, sirtuins, uncoupling protein 2 and antioxidant enzymes. Int. J. Biochem. Cell Biol. 2013, 45, 2045–2051.
  87. Voelcker, G.; Pfeiffer, B.; Schnee, A.; Hohorst, H.J. Increased antitumour activity of mesyl-I-aldophosphamide- perhydrothiazine, in vivo but not in vitro, compared to I-aldophosphamide- perhydrothiazine. J. Cancer Res. Clin. Oncol. 2000, 126, 74–78.
  88. Mai, Z.; Blackburn, G.L.; Zhou, J.R. Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Mol. Carcinog. 2007, 46, 534–542.
  89. Katdare, M.; Osborne, M.; Telang, N.T. Soy isoflavone genistein modulates cell cycle progression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial cells. Int. J. Oncol. 2002, 21, 809–815.
  90. Sharma, S.V.; Haber, D.A.; Settleman, J. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat. Rev. Cancer 2010, 10, 241–253.
  91. Romagnolo, D.F.; Donovan, M.G.; Papoutsis, A.J.; Doetschman, T.C.; Selmin, O.I. Genistein prevents BRCA1 CpG methylation and proliferation in human breast cancer cells with activated aromatic hydrocarbon receptor. Curr. Dev. Nutr. 2017, 1, e000562.
  92. Privat, M.; Aubel, C.; Arnould, S.; Communal, Y.; Ferrara, M.; Bignon, Y.J. Breast cancer cell response to genistein is conditioned by BRCA1 mutations. Biochem. Biophys. Res. Commun. 2009, 379, 785–789.
  93. Liggins, J.; Bluck, L.J.C.; Runswick, S.; Atkinson, C.; Coward, W.A.; Bingham, S.A. Daidzein and genistein contents of vegetables. Br. J. Nutr. 2000, 84, 717–725.
  94. McMichael-Phillips, D.F.; Harding, C.; Morton, M.; Roberts, S.A.; Howell, A.; Potten, C.S.; Bundred, N.J. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am. J. Clin. Nutr. 1998, 68, 1431S–1435S.
  95. Hargreaves, D.F. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J. Clin. Endocrinol. Metab. 1999, 84, 4017–4024.
  96. 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.; et al. Soy isoflavone supplementation for breast cancer risk reduction: A randomized phase ii trial. Cancer Prev. Res. 2012, 5, 309–319.
  97. Marini, H.; Minutoli, L.; Polito, F.; Bitto, A.; Altavilla, D.; Atteritano, M.; Gaudio, A.; Mazzaferro, S.; Frisina, A.; Frisina, N.; et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: A randomized trial. Ann. Intern. Med. 2007, 146, 839–847.
  98. D’Anna, R.; Cannata, M.L.; Atteritano, M.; Cancellieri, F.; Corrado, F.; Baviera, G.; Triolo, O.; Antico, F.; Gaudio, A.; Frisina, N.; et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: A 1-year randomized, double-blind, placebo-controlled study. Menopause 2007, 14, 648–655.
  99. Razandi, M.; Pedram, A.; Rosen, E.M.; Levin, E.R. BRCA1 Inhibits Membrane Estrogen and Growth Factor Receptor Signaling to Cell Proliferation in Breast Cancer. Mol. Cell. Biol. 2004, 24, 5900–5913.
  100. Tang, H.; Wang, S.; Li, X.; Zou, T.; Huang, X.; Zhang, W.; Chen, Y.; Yang, C.; Pan, Q.; Liu, H.-F. Prospects of and limitations to the clinical applications of genistein. Discov. Med. 2019, 27, 177–188.
  101. Bhadoriya, S.S.; Mangal, A.; Madoriya, N.; Dixit, P. Bioavailability and bioactivity enhancement of herbal drugs by ‘Nanotechnology’: A review. J. Curr. Pharm. Res. 2011, 8, 1–7.
  102. Patel, N.R.; Pattni, B.S.; Abouzeid, A.H.; Torchilin, V.P. Nanopreparations to overcome multidrug resistance in cancer. Adv. Drug Deliv. Rev. 2013, 65, 1748–1762.
  103. Peetla, C.; Vijayaraghavalu, S.; Labhasetwar, V. Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles. Adv. Drug Deliv. Rev. 2013, 65, 1686–1698.
  104. Rizwanullah, M.; Amin, S.; Mir, S.R.; Fakhri, K.U.; Rizvi, M.M.A. Phytochemical based nanomedicines against cancer: Current status and future prospects. J. Drug Target. 2018, 26, 731–752.
  105. Shukla, R.P.; Dewangan, J.; Urandur, S.; Banala, V.T.; Diwedi, M.; Sharma, S.; Agrawal, S.; Rath, S.K.; Trivedi, R.; Mishra, P.R. Multifunctional hybrid nanoconstructs facilitate intracellular localization of doxorubicin and genistein to enhance apoptotic and anti-angiogenic efficacy in breast adenocarcinoma. Biomater. Sci. 2020, 8, 1298–1315.
  106. Pham, J.; Grundmann, O.; Elbayoumi, T. Mitochondriotropic nanoemulsified genistein-loaded vehicles for cancer therapy. Methods Mol. Biol. 2015, 1265, 85–101.
  107. Cai, L.; Yu, R.; Hao, X.; Ding, X. Folate Receptor-targeted Bioflavonoid Genistein-loaded Chitosan Nanoparticles for Enhanced Anticancer Effect in Cervical Cancers. Nanoscale Res. Lett. 2017, 12, 509.
  108. Mei, L.; Zhang, H.; Zeng, X.; Huang, L.; Wang, Z.; Liu, G.; Wu, Y.; Yang, C. Fabrication of genistein-loaded biodegradable TPGS-b-PCL nanoparticles for improved therapeutic effects in cervical cancer cells. Int. J. Nanomed. 2015, 10, 2461–2473.
  109. Dev, A.; Sardoiwala, M.N.; Kushwaha, A.C.; Karmakar, S.; Choudhury, S.R. Genistein nanoformulation promotes selective apoptosis in oral squamous cell carcinoma through repression of 3PK-EZH2 signalling pathway. Phytomedicine 2021, 80, 153386.
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