Selenized milk casein in the diet of BALB/c nude mice reduces growth of intramammary MCF-7 tumors
© Warrington et al.; licensee BioMed Central Ltd. 2013
Received: 23 April 2013
Accepted: 8 October 2013
Published: 23 October 2013
Dietary selenium has the potential to reduce growth of mammary tumors. Increasing the Se content of cows’ milk proteins is a potentially effective means to increase Se intake in humans. We investigate the effects of selenized milk protein on human mammary tumor progression in immunodeficient BALB/c nude mice.
Four isonitrogenous diets with selenium levels of 0.16, 0.51, 0.85 and 1.15 ppm were formulated by mixing low- and high-selenium milk casein isolates with a rodent premix. MCF-7 cells were inoculated into the mammary fat pad of female BALB/c nude mice implanted with slow-release 17 β-estradiol pellets. Mice with palpable tumors were randomly assigned to one of the four diets for 10 weeks, during which time weekly tumor caliper measurements were conducted. Individual growth curves were fit with the Gompertz equation. Apoptotic cells and Bcl-2, Bax, and Cyclin D1 protein levels in tumors were determined.
There was a linear decrease in mean tumor volume at 70 days with increasing Se intake (P < 0.05), where final tumor volume decreased 35% between 0.16 and 1.15 ppm Se. There was a linear decrease in mean predicted tumor volume at 56, 63 and 70 days, and the number of tumors with a final volume above 500 mm3, with increasing Se intake (P < 0.05). This tumor volume effect was associated with a decrease in the proportion of tumors with a maximum growth rate above 0.03 day-1. The predicted maximum volume of tumors (Vmax) and the number of tumors with a large Vmax, were not affected by Se-casein. Final tumor mass, Bcl-2, Bax, and Cyclin D1 protein levels in tumors were not significantly affected by Se-casein. There was a significantly higher number of apoptotic cells in high-Se tumors as compared to low-Se tumors.
Taken together, these results suggest that turnover of cells in the tumor, but not its nutrient supply, were affected by dairy Se. We have shown that 1.1 ppm dietary Se from selenized casein can effectively reduce tumor progression in an MCF-7 xenograft breast cancer model. These results show promise for selenized milk protein as an effective supplement during chemotherapy.
KeywordsSelenium Casein Mammary tumor MCF-7 cells
Selenium is an essential trace mineral that is required at greater than 0.15 ppm in the diet of humans and laboratory animals to maximize synthesis of selenoproteins . Se becomes toxic at levels greater than 400 ug /d in the diet and deficient at levels lower than 40 ug/d. Supranutritional supplementation of seleniumat 1 to 4 ppm has shown great promise in cancer prevention [2, 3], though the mechanism of the effect remains elusive. Transformed cells are often able to persist and replicate due to a disruption in the regulatory circuitry controlling programmed cell death. Both organic and inorganic forms of Se have been observed to induce apoptosis in several cancer cell lines in vitro, including human prostate cancer cells, human leukemia cells, and murine mammary epithelial cells [4–8].
Due to the global variation in soil Se content, there exist Se-deficient populations in the world  Further, those populations that receive adequate levels of Se in their diet are likely still below the level of Se required to prevent cancer . Increasing the selenium content of cow’s milk has been suggested to be an effective way of improving selenium intake in humans. The supplementation of Se-yeast in a cow’s diet is the most effective method for increasing milk Se content, where Se is incorporated into milk proteins as selenomethionine during milk synthesis . Consumption of 1 ppm Se from selenized milk protein increased apoptosis and decreased proliferation of chemically induced colon tumors, and decreased the number of mice with tumors 30 weeks after carcinogen exposure . Effects of dairy Se on mammary tumor development has not previously been investigated although organic forms of Se providing 2 ppm dietary Se decreased by 50% the number of chemically induced mammary tumors 22 weeks after carcinogen exposure in rats .
The objective of this study was to investigate the effects of selenized milk protein on human mammary tumor progression in immunodeficient BALB/c nude mice. The effects of selenized milk protein on apoptotic circuitry in these human epithelial MCF-7 breast tumor cells were also investigated. We found that each increment in Se intake between 0.16 and 1.15 ppm of diet dry matter caused a decrease in tumor volume after 8 weeks on diets.
Estrogen receptor-positive MCF-7 breast cancer cells were cultured in Eagle’s Minimum Essential Medium (ATCC Catalog No. 30–2003) supplemented with 0.01 mg/mL human insulin and 10% fetal bovine serum. Cells were incubated at 37°C and 5% CO2 in air atmosphere. Passage was conducted when cells reached confluency every two to three days. Cells were collected for injection at 80% confluency by centrifuging at 125 xg for 5 minutes. Cells were suspended in 50% Matrigel™ Basement Membrane Matrix (BD Biosciences, Mississauga, ON), 50% media at a final concentration of 3 × 106 cells/100 uL.
Casein isolation and diet formulation
To generate low- and high-Se caseins, Holstein dairy cows were fed 0 or 4.5ppm (dry basis) selenium as Se-yeast (Sel-Plex, Alltech Inc., Kentucky, USA) on top of a basal diet of 0.15 ppm Se from Na2SeO3. Diets were fed for 3 weeks, after which milk was collected and stored at 4°C until pasteurized and skimmed at 70°C with a flow rate of 1.5L/min. The skim milk was cooled to 45°C and an acid casein precipitate was formed by adding lactic acid (88% food grade) to a pH of 4.6. The casein precipitate was washed twice with cold deionized water, collected on cheese cloth, and drained overnight. The casein was separated into trays and freeze dried at −20°C for 3 days. The product was then ground and stored at 4°C.
Composition of experimental diets
(g/100 g diet)
Mineral mix, no added Se
Calcium phosphate dibasic
Potassium citrate H2O
All mice were housed and cared for according to guidelines established by the Animal Care Committeeat the University of Guelph and the Canadian Council on Animal Care. Seventy-two female, athymic, BALB/c nude mice, 6–8 weeks old, were purchased from Charles River Laboratories (Senneville, QC). Mice were housed in autoclaved, ventilated cages and provided with autoclaved water. Water and food were offered ad libitum. Food consumption was not measured, however body weights were measured biweekly throughout the trial. They were exposed to a 12-hour light/12-hour dark cycle and fed standard mouse chow (Research Diets, New Brunswick, NJ) once daily at 1800 h. After 1 week of acclimatization, mice were xenotransplanted under isoflurane anaeasthesia with 3 x 106 MCF-7 cells in the mammary fat pad and 90-day release 17β-estradiol pellets (0.5 mg/pellet; Innovative Research of America, Sarasota, FL) subcutaneously between scapulae.
Beginning one week post-surgery, tumor volumes were assessed daily using caliper measurements. Tumor volumes (V) were calculated as V = l × w2/2, where l is length and w is width of the tumor. Once tumor volume reached approximately 60 mm3 mice were randomized to one of the four treatment diets. Only mice with tumors that reached a palpable volume within 3 weeks after implantation were included in the trial. The animal trial involved 72 mice; 18 mice per diet. 7, 8, 4, and 5 mice from treatments 1, 2, 3, and 4, respectively, were euthanized during this trial. These mice were prematurely euthanized for exhibiting criteria for euthanasia; either clinical signs or because tumor size exceeded 10% of body weight. Each cage of 5 mice was furnished with 2 plastic feeders that were replaced at 1200 h daily with 10 g powdered diet.
After 10 weeks on experimental diets, mice were sacrificed by CO2 asphyxiation, and tumors and livers were excised, weighed and frozen in liquid nitrogen prior to storage at −80°C. A section of tumor was also stored in 10% formalin solution for at least 24 hours, after which it was embedded in paraffin wax.
Western blots were performed on tumor tissue from each subject to measure levels of cyclin D1, Bcl-2, and Bax. Tumor tissues were homogenized in 2 μL RIPA lysis buffer/mg tissue, containing 10 μL/mL protease inhibitor. Protein concentrations in tissue homogenates were measured according to Bradford (1976) with bovine serum albumin as the standard. Membranes were blocked for one hour with 5% (wt/vol) skim milk at 4°C and incubated with rabbit anti-cyclin D1 (1:1000 dilution, Cell Signaling, Danvers, MA), rabbit anti-Bcl-2 (1:1000 dilution, Cell Signaling, Danvers, MA), rabbit anti-Bax (1:1000 dilution, Cell Signaling, Danvers, MA) or rabbit anti-β-tubulin (1:1000 dilution, Cell Signaling, Danvers, MA) on a rocking platform. After washing with TBST (TBS, 1% (vol/vol) Tween 20), membranes were incubated with peroxidase-conjugated anti-rabbit secondary antibody (1:2000 dilution, Cell Signaling, Danvers, MA) for 1 hour at room temperature on a rocking platform. Immunoreactive proteins were visualized by chemiluminescence (ECL Western Blotting Detection Reagents) using horseradish peroxidase-linked secondary antibody (anti-rabbit immunoglobulin, 1:2000 dilution). β-tubulin was used to normalize protein loads between blots.
Detection of apoptosis
Wax-embedded tissues from the 4 largest tumors on each treatment were sectioned at 5 μm onto polarized slides for colorimetric TUNEL assay. To visualize and quantify tumor cell death, TUNEL assay was performed using an in situ Cell Death Detection Kit (Promega, Madison, WI, USA) according to the manufacturer’s protocol. Nuclei were counterstained using Harris-modified hematoxylin, and slides were mounted. The number of apoptotic cells was expressed as a percentage of total cells, counting 1500–2000 nuclei per sample.
Tumor samples were freeze-dried and digested in nitric acid in a 90°C sand bath. The digestate was then brought up to volume (10mL) and analyzed using Inductively Coupled Plasma Mass Spectroscopy (AOAC, 2005). Selenium values are reported on a dry matter basis.
where predi is the i-th prediction, obsi is the i-th observation, and n is the number of observations.
Tumor growth dynamics
Gompertz fits to tumor growth curves and parameter estimates.
Dietary Se level (μg/g dry matter)
rMSPE (% of mean)
Effects of Se-casein on tumor growth were also evaluated by counting the number of large and fast-growing tumors on each treatment. The proportion of tumors with a final volume above 500 mm3 (Figure 1a) and the proportion of tumors with a maximum growth rate above 0.03 d-1 (Figure 1b) were both linearly decreased by Se inclusion level (P exact< 0.02). Proportions of tumors with a large Vmax, tinflection, or specific growth rate at 70 days were not affected by treatment (Figure 1c - e).
The level of cyclin D1 expression was chosen as a marker of cell proliferation, as it is commonly over-expressed in breast cancer cells [14, 15]. Western blot analysis of tumor tissue from each mouse subject did not reveal a significant difference in cyclin D1 expression between treatments (Figure 7d).
Our findings show, for the first time, that dietary Se is effective at reducing growth of human mammary tumors in situ. The tumors originated from MCF-7 cells implanted in the mammary stroma of immune-compromised mice. The dietary Se was provided in casein isolated from the milk of cows fed Se-yeast in their diet. Increasing dietary Se from 0.16 to 1.15 ppm caused a linear decrease in tumor volumes and the number of large tumors after 8 weeks (tumors with Vfinal > 500 mm3). The tumor volume effect was associated with a decrease in the number of tumors with a fast maximum growth rate. Although these observations indicate that growth rate was reduced, the maximum volume that tumors were predicted to reach (Vmax), and the number of tumors with a large Vmax, were not affected by Se-casein. Maximum volume and growth rate were generated using Gompertz fits of the observed growth data. Growth rate of tumors is related to the net difference between proliferation and death of individual cells, while final volume is related to the ability to maintain oxygen and nutrient supply to the tumor, particularly its inner core . Thus, Se-casein appears to affect cancer cell turnover but not supply or extraction of nutrients by the tumor.
Our results add a new dimension to the findings that dietary Se prevents oncogenesis in chemical-induction models of mammary and colorectal cancer [6, 12], and to the growing body of evidence that Se compounds are effective against established tumors . Selenium is thought to affect tumor growth by inducing cell cycle arrest and apoptosis [18–20]. Generally speaking, inorganic selenium is reduced to hydrogen selenide which results in reactive oxygen species-mediated induction of single-strand DNA breaks and apoptosis in various cancer cell lines, including leukemia, mammary and prostate cancers [21–23]. Organic selenium sources, on the other hand, are able to induce apoptosis without the genotoxic effects, ostensibly via the metabolite methylselenol . Putative mechanisms by which methylselenol prevents cancer include caspase activation and dephosphorylation of pro-survival Akt and extracellular signal-related kinase 1/2 .
Casein isolated from the milk of cows fed Se-yeast contains organic Se, primarily in the forms of selenomethionine and selenocysteine . These organic forms of Se are readily concentrated in tissues because of sequestration in proteins. In the current study, tumors from mice fed 1.15 ppm Se-casein accumulated an average Se concentration of 4.58 ppm, whereas s.c. injection of 1.5 ppm inorganic Se as selenite in a previous study resulted in MCF-7 tumor Se concentrations of 1.55 ppm . Whether the higher tumor Se concentration due to Se-casein consumption translates into greater exposure to hydrogen selenide or methylselenol remains unknown. However, we observed a significantly higher number of apoptotic cells in high-Se tumors as compared to low-Se tumors. In vitro, the IC50 of SeMet against MCF-7 cells was 45 μM . Assuming it is all SeMet, the 4.58 ppm Se we found in mammary tumors is equivalent to a concentration of 23 μM SeMet. The 35% decrease in final tumor volume we observed on the high-Se diet is consistent with tumor Se concentrations slightly less than the IC50. The pro-apoptotic effect of Se on cancer cells in vitro and in vivo is well documented [5, 6, 17] but effects of dietary Se on apoptosis in human mammary tumors have not previously been reported.
Redman and coworkers  investigated the effects of SeMet on four cell lines in vitro: MCF-7 breast carcinoma, UACC-375 melanoma, DU-145 prostate cancer, as well as normal diploid fibroblasts. This study investigated the IC50 of SeMet for for each cell line. SeMet concentrations ranged from 100–10000 μM. SeMet inhibited growth in all cell lines in a dose-dependent manner. In MCF-7 cells, cell viability was not affected by 0.01-10 μM, while 100–1000 μM significantly inhibited cell growth. In UACC-375 melanoma cells, concentrations greater than 1 μM were required to significantly inhibit cell growth. In prostate cancer cells DU-145, concentrations beyond 10 μM showed a marked decline in cell growth. In contrast to the micromolar concentrations of SeMet shown to inhibit cancer cell lines, inhibition of growth in diploid fibroblasts required millimolar concentrations. These results indicated that DU-145 prostate cancer cells are the most sensitive to SeMet treatment with a IC50 of 40 μM, followed by MCF-7 and UACC-375 with 45 μM and 50 μM, respectively. Fibroblasts required 1 mM SeMet to induce 50% inhibition. According to these results, cancer cells may be more sensitive to selenium treatment than normal cells . It was postulated that these discrepancies may be due to differences in uptake and metabolism of SeMet to anticarcinogenic metabolites, as SeMet may be metabolized to methylselenol or SeCys, which in turn is hydrolyzed to hydrogen selenide .
Similar to Kaeck et al. , we found no effect of Se on Bax or Bcl-2 expression in tumors, despite an increase in apoptosis. In contrast, MSeA increased Bax and decreased Bcl-2 expression in three lines of prostate cancer cells . While Bcl-2 and Bax are considered the main players in controlling programmed cell death, apoptosis is an intricate process with several points of control that have been shown to be affected by Se, including expression of Bcl-x1, Bak and Bid [28, 29]. The results herein indicate that Se-casein was able to induce apoptosis in MCF-7 cells independently of the Bax:Bcl-2 rheostat, suggesting an alternative apoptotic pathway is being targeted.
In addition to apoptosis, tumor growth is determined by cell proliferation. Se is known to downregulate several genes controlling the expression of cell cycle proteins, including cyclins A and cyclin D1 . Cyclin D1 is an important regulator in the early stages of the cell cycle, controlling the transition from the first gap phase to the synthesis phase. We chose cyclin D1 as a marker of tumor proliferation. While this protein is overexpressed in over half of breast cancer cases,cyclin D1 levels in MCF-7 cells are similar to those found in normal mammary epithelial cells [14, 15, 30], yet cyclin D1 has been shown to play an essential role in cell cycle progression in MCF-7 cells . We observed no effect of Se-casein treatment on cyclin D1 expression. In vitro study shows that 5 μM MSeA downregulates cyclin D1 in premalignant human breast cells at an early time-point and upregulates cyclin D1 at a later time point . Thus, interruption of cyclin D1-mediated cell cycle progression does not appear to be responsible for the inhibitory effects of Se-casein on tumor growth observed in the current study. Selenium, however, has been shown to downregulate several genes controlling the expression of cell cycle proteins, including cyclin A, CDC25A, CDK4, PCNA and E2F .
Many different forms of dietary Se have been tested for efficacy against the development and progression of cancer including SeMet, MSeA, SeMSC (Se-methylselenocysteine), and Se-enriched broccoli, garlic and milk protein [6, 12, 27, 34, 35]. The highest dose of Se we administered via dietary casein was 1.15 ppm, which was insufficient to cause more than a 35% decrease in tumor growth. However, the linearity of the response to dose suggests that higher doses could have a greater inhibitory effect. Organic Se doses up to 5 ppm Se have been fed to animals in studies of cancer chemoprevention. Another option might be to use Se-casein in conjunction with other chemotherapeutics. Se appears to sensitize cancer cells to apoptosis while reducing the toxic effects of therapy and selectively protecting normal cells . For instance, Li et al.  showed that Se in the form of MSeA sensitized MCF-7 cells to doxorubicin-induced apoptosis . Another study found that MSeA acted synergistically with paclitaxel in the treatment of triple-negative breast cancer to increase induction of caspase-mediated apoptosis, cell cycle arrest, and inhibition of cell proliferation .
We have shown that 1.15 ppm dietary Se from selenized casein can effectively reduce tumor progression in an MCF-7 xenograft breast cancer model. Results of a DNA nick-end labeling assay support the claim that Se-casein reduces breast cancer cell growth by increasing the number of cells undergoing apoptosis.The literature indicates that the optimal Se intake is 250 – 300 ug per day, however the interaction of Se with other elements must be considered . These elements include, but are not limited to, As, Cu, Ni, Co, Cr, Mn, Zn, Cd, Sn, Pb, Hg, Bi, Mo, Ag, and Au, Evidence from animal experiments suggest that chronic exposure to these elements counteracts the anticarcinogenic effects of Se . This indicates that the presence of these elements in the diet must be well characterized before a claim can be made regarding Se-casein as a cancer-protective supplement.
While the average Se intake in most countries is sufficient to prevent Se deficiencies, it may be suboptimal for protection against a number of adverse health conditions. This is because the amount of selenium in the human diet is largely dependent on the soil content where crops destined for human consumption are cultivated. Therefore, providing Se-enriched casein through milk has the potential to not only prevent deficiency, but also provide the supranutritional levels required to prevent a disease like cancer. This study showed the potential for Se-casein to be an effective treatment of breast cancer, suggesting its potential role in adjuvant therapy. Further study is required to elucidate the precise mechanism through which supranutritional Se-casein levels reduce carcinogenesis. The effects of high-Se casein on normal cells in addition to cancerous cells should also be well-characterized before it may be approved as an effective dietary supplement for chemoprevention in order to eliminate safety concerns.
Increasing dietary Se from 0.16 to 1.15 ppm caused a linear decrease in tumor volumes and the number of large tumors after 8 weeks. The tumor volume effect was associated with a decrease in the number of tumors with a fast maximum growth rate, however the maximum volume that tumors were predicted to reach and the number of tumors with a large maximum volume were not affected by Se-casein. Taken together, this suggests that dairy Se affects the turnover of cells in the tumor, but not its nutrient supply. We have shown that 1.1 ppm dietary Se from selenized casein can effectively reduce tumor progression in an MCF-7 xenograft breast cancer model. These results show promise for selenized milk protein as an effective supplement during the course chemotherapy.
Protein Kinase B
Bcl-2 homologous antagonist killer
Bcl-2 associated X protein
B-cell lymphoma 2
Half maximal inhibitory concentration
Terminal deoxynucleotidyltransferasedUTPnick end labeling.
We thank the staff at Elora Dairy Research Centre who contributed to cow feeding and milk acquisition and the Guelph Food and Technology Centre staff at the University of Guelph participated who assisted with milk processing. We thank the Central Animal Facility staff for their excellent animal care and, in particular, Jackie Rombeek who participated in animal care and surgery and Marcus Litman for acting as our veterinary consultant. Financial support was provided by Dairy Farmers of Ontario, Alltech Canada, Inc., and NSERC Canada.
- Wycherly BJ, Moak MA, Christensen MJ: High dietary intake of sodium selenite induces oxidative DNA damage in rat liver. Nutr Cancer. 2004, 48: 78-83. 10.1207/s15327914nc4801_11.View ArticlePubMedGoogle Scholar
- Yoshizawa K, Willet WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, Giovannucci E: Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst. 1998, 90: 1219-1224. 10.1093/jnci/90.16.1219.View ArticlePubMedGoogle Scholar
- Clark LC, Combs GF, Turnbull BW, Slate EH, Chalker DK, Chow J, Davis LS, Glover RA, Graham GF, Gross EG, Krongrad A, Lesher JL, Park HK, Sanders BB, Smith CL, Taylor JR: Effect of selenium supplementation for cancer prevention in patients with carcinoma of the skin. J Am Med Assoc. 1996, 276: 1957-1963. 10.1001/jama.1996.03540240035027.View ArticleGoogle Scholar
- Jiang C, Wang Z, Ganther H, Lu J: Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways inDU145 human prostate cancer cells. Mol Cancer Ther. 2002, 1: 1059-1066.PubMedGoogle Scholar
- Kim T, Jung U, Cho D, Chung A: Se-Methylselenocysteine induces apoptosis through caspase activation in HL-60 cells. Carcinogenesis. 2001, 22 (4): 559-565. 10.1093/carcin/22.4.559.View ArticlePubMedGoogle Scholar
- Ip C, Thompson HJ, Zhu Z, Ganther HE: In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention. Cancer Res. 2000, 60: 2882-2886.PubMedGoogle Scholar
- Sinha R, Medina D: Inhibition of cdk2 kinase activity by Semethylselenocysteine in synchronized mouse mammary epithelial cells. Carcinogenesis. 1997, 18: 1541-1547. 10.1093/carcin/18.8.1541.View ArticlePubMedGoogle Scholar
- Sinha R, Unni E, Ganther HE, Medina D: Methylseleninic acid, a potent growth inhibitor of synchronized mouse mammary epithelial tumor cells in vitro. BiochemPharmacol. 2000, 61: 311-317.Google Scholar
- Rayman MP: Selenium in cancer prevention: a review of the evidence and mechanism of action. Proc Nutr Soc. 2005, 64: 527-542. 10.1079/PNS2005467.View ArticlePubMedGoogle Scholar
- Combs GF: Should intakes with beneficial actions, often requiring supplementation, be considered for RDAs?. J Nutr. 1996, 126: 2373-2376.Google Scholar
- Phipps RH, Grandison AS, Jones AK, Juniper DT, Ramos-Morales E, Bertin G: Selenium supplementation of lactating dairy cows: effects on milk production and total selenium content and speciation in blood, milk and cheese. Animal. 2008, 2 (11): 1610-1618. 10.1017/S175173110800298X.View ArticlePubMedGoogle Scholar
- Hu Y, McIntosh GH, Le Leu RK, Woodman R, Young GP: Suppression of colorectal oncogenesis by selenium-enriched milk proteins: apoptosis and K-ras mutations. Cancer Res. 2008, 68: 4936-4944. 10.1158/0008-5472.CAN-07-6042.View ArticlePubMedGoogle Scholar
- Chignola R, Schenetti A, Andrighetto G, Chiesa E, Foroni R, Sartoris S, Tridente G, Liberati D: Forecasting the growth of multicell tumour spheroids: implication for the dynamic growth of solid tumours. Cell Prolif. 2000, 33: 219-229. 10.1046/j.1365-2184.2000.00174.x.View ArticlePubMedGoogle Scholar
- Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicolson RI, Defazio A, Watts CK, Musgrove EA, Sutherland RL: Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993, 8: 2127-2133.PubMedGoogle Scholar
- van Diest PJ, Michalides RJAM, Jannink I, van der Valk P, Peterse HL, de Jong JS, Meijer CJLM, Baak JPA: Cyclin D1 expression in invasive breast cancer: correlations and prognostic value. Am J Pathol. 1997, 150: 705-711.PubMedPubMed CentralGoogle Scholar
- Kiran KL, Jayachandran D, Lakshminarayanan S: Mathematical modelling of avascular tumour growth based on diffusion of nutrients and its validation. CanSocChemEng. 2009, 87: 732-740.Google Scholar
- Li Z, Latonya C, Belame A, Thiyagarajah A, Salvo AA, Burow ME, Rowan BG: Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis. Breast Cancer Res Treat. 2009, 118: 33-43. 10.1007/s10549-008-0216-x.View ArticlePubMedGoogle Scholar
- Whanger PD: Selenium and its relationship to cancer: an update. Br J Nutr. 2004, 91: 11-28. 10.1079/BJN20031015.View ArticlePubMedGoogle Scholar
- Ip C: Lessons from basic research in selenium and cancer prevention. J Nutr. 1998, 128: 1845-1854.PubMedGoogle Scholar
- El-Bayoumy K, Sinha R: Molecular chemoprevention by selenium: A genomic approach. Mutation Res. 2005, 591: 224-236. 10.1016/j.mrfmmm.2005.04.021.View ArticlePubMedGoogle Scholar
- Lu J, Kaeck M, Jiang C, Wilson AC, Thompson HJ: Selenite induction of DNA strand breaks and apoptosis in mouse leukemic L1210 cells. BiochemPharmacol. 1994, 47: 1531-1535.Google Scholar
- Thompson HJ, Wilson A, Lu JX, Singh M, Jiang C, Upadhyaya P, El- Bayoumy K, IpC: Comparison of the effects of an organic and an inorganic form of selenium on a mammary carcinoma cell line. Carcinogenesis. 1994, 15: 183-186. 10.1093/carcin/15.2.183.View ArticlePubMedGoogle Scholar
- Jiang C, Wang Z, Ganther H, Lu J: Caspases as key executors of methyl selenium-induced apoptosis (anoikis) ofDU-145 prostate cancer cells. Cancer Res. 2001, 61: 3062-3070.PubMedGoogle Scholar
- Wang Z, Jiang C, Lu J: Induction of caspase-mediated apoptosis and cell-cycle G1 arrest by selenium metabolite methylselenol. Mol Carcinog. 2002, 34: 113-120. 10.1002/mc.10056.View ArticlePubMedGoogle Scholar
- Watrach AM, Milner JA, Watrach MA, Poirier KA: Inhibition of human breast cancer cells by selenium. Cancer Lett. 1984, 25: 41-47. 10.1016/S0304-3835(84)80024-5.View ArticlePubMedGoogle Scholar
- Redman C, Scott JA, Baines AT, Basye JL, Clark LC, Calley C, Roe D, Payne CM, Nelson MA: Inhibitory effect of selenomethionine on the growth of three selected human tumor cells lines. Cancer Lett. 1998, 125: 103-110. 10.1016/S0304-3835(97)00497-7.View ArticlePubMedGoogle Scholar
- Kaeck M, Lu J, Strange R: Differential induction of growth arrest inducible genes by selenium compounds. Biochem Pharmacol. 1997, 53: 921-926. 10.1016/S0006-2952(97)00103-2.View ArticlePubMedGoogle Scholar
- Reagan-Shaw S, Nihal M, Ahsan H, Mukhtar H, Ahmad N: Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio. Prostate. 2008, 68: 1624-1634. 10.1002/pros.20824.View ArticlePubMedPubMed CentralGoogle Scholar
- Chen T, Wong Y: Selenocystine induces caspase-independent apoptosis in MCF-7 human breast carcinoma cells with involvement of p53 phosphorylation and reactive oxygen species generation. Int J Biochem Cell Biol. 2009, 41: 666-676. 10.1016/j.biocel.2008.07.014.View ArticlePubMedGoogle Scholar
- Zwijsen RML, Klompmaker R, Weintjens EBHGM, Kristel PMP, van der Burg B, Michalides RJAM: Cyclin D1 triggers autonomous growth of breast cancer cells by governing cell cycle exit. Mol Cell Biol. 1996, 16: 2554-2560.View ArticlePubMedPubMed CentralGoogle Scholar
- Bartkova J, Lukas J, Müller H, Lutzhoft D, Strauss M, Bartek J: Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994, 57: 353-361. 10.1002/ijc.2910570311.View ArticlePubMedGoogle Scholar
- Dong Y, Ganther HE, Stewart C, Ip C: Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res. 2002, 62: 708-714.PubMedGoogle Scholar
- El-Bayoumy K, Sinha R: Molecular chemoprevention by selenium: A genomic approach. Mutat Res. 2005, 591: 224-236. 10.1016/j.mrfmmm.2005.04.021.View ArticlePubMedGoogle Scholar
- Finley JW, Davis CD, Feng Y: Selenium from high selenium broccoli protects rats from colon cancer. J Nutr. 2000, 130: 2384-2389.PubMedGoogle Scholar
- Ip C, Lisk DJ, Thompson HJ: Selenium-enriched garlic inhibits the early stage but not the late stage of mammary carcinogenesis. Carcinogenesis. 1996, 17: 1979-1982. 10.1093/carcin/17.9.1979.View ArticlePubMedGoogle Scholar
- Cao S, Durrani FA, Rustum YM: Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin Cancer Res. 2004, 10: 2561-2569. 10.1158/1078-0432.CCR-03-0268.View ArticlePubMedGoogle Scholar
- Li S, Zhou Y, Wang R, Zhang H, Dong Y, Ip C: Selenium sensitizes MCF-7 breast cancer cells to doxorubicin-induced apoptosis through modulation of phospho-Akt and its downstream substrates. Mol Cancer Ther. 2007, 6: 1031-1038.View ArticlePubMedGoogle Scholar
- Qi Y, Fu X, Xiong Z, Zhang H, Hill SM, Rowan BG, Dong Y: Methylseleninic acid enhances paclitaxel efficacy for the treatment of triple-negative breast cancer. PLoS ONE. 2001, 7 (2): e31539-doi:10.1371/journal.pone.0031539View ArticleGoogle Scholar
- Schrauzer GN: Selenium and selenium-antagonistic elements in nutritional cancer prevention. Crit Rev Biotechnol. 2009, 29 (1): 10-17. 10.1080/07388550802658048.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/492/prepub
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