Rola metalotionein i kadmu w rozwoju raka piersi

• Authors: Ewa Forma , Magdalena Bryś

Title variants

EN

Role of metalothioneins and cadmium in breast carcinogenesis

• Languages of publication: PL

Abstracts

PL

Metalotioneina (MT) została po raz pierwszy odkryta ponad 50 lat temu, jako białko wiążące kadm w nerce konia. Metalotioneiny są grupą powszechnie występujących białek o niskiej masie cząsteczkowej, wysokiej zawartości reszt cysteiny, których grupy tiolowe wiążą jony takich metali jak kadm (Cd), cynk (Zn) i miedź (Cu). U ssaków wyróżnia się cztery izoformy metalotioneiny oznaczone jak MT-1 – MT-4. Do podstawowych funkcji metalotionein zalicza się utrzymanie homeostazy metali ciężkich, ochronę przed ich toksycznym działaniem, a także ochronę przed stresem oksydacyjnym. Kadm, który został zakwalifikowany do substancji karcynogennych I klasy, może między innymi stymulować proliferację komórek, hamować naprawę uszkodzeń DNA, zaburzać proces apoptozy oraz promować rozwój nowotworów w licznych tkankach. Kadm znajdujący się w środowisku naturalnym pochodzi ze źródeł naturalnych, jak i antropogenicznych, przy czym ilość kadmu dostająca się do środowiska w wyniku działalności człowieka od 3 do 10 razy przekracza ilości kadmu pochodzące ze źródeł naturalnych. Kadm akumuluje się w organizmie człowieka, a jego okres biologicznego półtrwania wynosi od 10 do 30 lat. Zarówno akumulacja Cd, jak i zaburzenia ekspresji metalotionein mogą mieć związek z rozwojem wielu typów nowotworów, w tym raka piersi.

EN

Metallothionein (MT) was first discovered over 50 years ago, as a cadmiumbinding protein in the kidney of a horse. Metallothioneins are a class of ubiquitously occurring cysteine and metal-rich proteins of low molecular weight, containing sulfur-based metal clusters formed with zinc (Zn), cadmium (Cd), and copper (Cu). In mammals, four distinct MT isoforms designated MT-1 – MT-4 are identified. The major physiological functions of metallothioneins include the homeostasis of essential metals Zn and Cu and the protection against oxidative stress and toxic effects of heavy metals such as Cd. Cadmium ,which has been classified as class I carcinogen, can stimulate cell proliferation, inhibit DNA repair, impair apoptosis and promote the development of cancer in a number of tissues. Significant quantities of Cd are introduced into the environment both by natural and anthropogenic activities, with anthropogenic activities contributing 3–10 times more Cd to the environment than natural activities. Cadmium accumulates in the human body with a long biological half-life ranging from 10 to 30 years. Cd accumulation and the aberrant expression of MTs have been found to be associated with the development of many types of cancers, including breast cancer.

Keywords

EN

breast cancer; cadmium; kadm; metallothioneins; metalotioneiny; rak piersi

Discipline

• MEDICINE: MEDICINE

• Publisher: Łódzkie Towarzystwo Naukowe
• Journal: Folia Medica Lodziensia
• Year: 2012
• Volume: 39
• Issue: 2
• Pages: 207-244

Contributors

author

Ewa Forma

• Katedra Cytobiochemii, Wydział Biologii i Ochrony Środowiska Uniwersytet Łódzki

author

Magdalena Bryś

• Katedra Cytobiochemii, Wydział Biologii i Ochrony Środowiska Uniwersytet Łódzki

References

• Arriaga JM, Levy EM, Bravo AI, Bayo SM, Amat M, Aris M i wsp. Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival. Hum Pathol. 2012; 43: 197-208.
• Sabolic I, Breljak D, Skarica M, Herak-Kramberger CM. Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals. 2010; 23: 897-926.
• Babula P, Masarik M, Adam V, Eckschlager T, Stiborova M, Trnkova L i wsp. Mammalian metallothioneins: properties and functions. Metallomics. 2012; 4: 739-750.
• Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and human health: an update. Arch Toxicol. 2012; 86: 521-534.
• Hartwig A. Mechanisms in cadmium-induced carcinogenicity: recent insights. Biometals. 2010; 23: 951-960.
• Joseph P. Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol. 2009; 238: 272-279.
• Waisberg M, Joseph P, Hale B, Beyersmann D. Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology. 2003; 192: 95-117.
• Werynska B, Pula B, Muszczynska-Bernhard B, Gomulkiewicz A, Piotrowska A, Prus R i wsp. Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients. Exp Mol Pathol. 2012;
• 94: 301-308.
• Forma E, Krzeslak A, Wilkosz J, Jozwiak P, Szymczyk A, Rozanski W i wsp. Metallothionein 2A genetic polymorphisms and risk of prostate cancer in a Polish population. Cancer Genet. 2012; 205: 432-435.
• Gumulec J, Masarik M, Krizkova S, Hlavna M, Babula P, Hrabec R i wsp. Evaluation of alpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers. Neoplasma. 2012; 59: 191-201.
• Yan DW, Fan JW, Yu ZH, Li MX, Wen YG, Li DW, Zhou CZ, Wang XL, Wang Q, Tang HM, Peng ZH. Downregulation of metallothionein 1F, a putative oncosuppressor, by loss of heterozygosity in colon cancer tissue. Biochim Biophys Acta. 2012; 1822: 918-926.
• Schöpfer J, Drasch G, Schrauzer GN. Selenium and cadmium levels and ratios in prostates, livers, and kidneys of nonsmokers and smokers. Biol Trace Elem Res. 2010; 134: 180-187.
• Sakamoto LH, DE Camargo B, Cajaiba M, Soares FA, Vettore AL. MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Pediatr Res. 2010; 67: 387-393.
• Vašák M, Meloni G. Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem. 2011; 16: 1067-1078.
• Cherian MG, Jayasurya A, Bay BH. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res. 2003; 533: 201-209.
• Palacios O, Atrian S, Capdevila M. Zn- and Cu-thioneins: a functional classification for metallothioneins? J Biol Inorg Chem. 2011; 16: 991-1009.
• Cai B, Zheng Q, Teng XC, Chen D, Wang Y, Wang KQ i wsp. The role of Thr5 in human neuron growth inhibitory factor. J Biol Inorg Chem. 2006; 11: 476-482.
• Romero-Isart N, Vašák M. Advances in the structure and chemistry of metallothioneins. J Inorg Biochem. 2002; 88: 388-396.
• Vašák M. Advances in metallothionein structure and functions. J Trace Elem Med. Biol. 2005; 19: 13-17.
• Coyle P, Philcox JC, Carey LC, Rofe AM. Metallothionein: the multipurpose protein. Cell Mol Life Sci. 2002; 59: 627-647.
• Jin R, Huang J, Tan PH, Bay BH. Clinicopathological significance of metallothioneins in breast cancer. Pathol Oncol Res. 2004; 10: 74-79.
• Sutherland DE, Summers KL, Stillman MJ. Noncooperative metalation of metallothionein 1a and its isolated domains with zinc. Biochemistry. 2012; 51: 6690-700.
• Maret W. The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr. 2000; 130(5S Suppl): 1455-1458
• Rigby KE, Stillman MJ. Structural studies of metal-free metallothionein. Biochem Biophys Res Commun. 2004; 325: 1271-1278.
• Haq F, Mahoney M, Koropatnick J. Signaling events for metallothionein induction. Mutat Res. 2003; 533: 211-226.
• Davis SR, Cousins RJ. Metallothionein expression in animals: a physiological perspective on function. J Nutr. 2000; 130: 1085-1088.
• Tapiero H, Tew KD. Trace elements in human physiology and pathology: zinc and metallothioneins. Biomed Pharmacother. 2003; 57: 399-411.
• Jayasurya A, Bay BH, Yap WM, Tan NG, Tan BK. Proliferative potential in nasopharyngeal carcinoma: correlations with metallothionein expression and tissue zinc levels. Carcinogenesis. 2000; 21: 1809-1812.
• Méplan C, Richard MJ, Hainaut P. Metalloregulation of the tumor suppressor protein p53: zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells. Oncogene. 2000; 19: 5227-5236.
• Kim CH, Kim JH, Lee J, Ahn YS. Zinc-induced NF-kappaB inhibition can be modulated by changes in the intracellular metallothionein level. Toxicol Appl Pharmacol. 2003; 190: 189-196.
• Tanji K, Irie Y, Uchida Y, Mori F, Satoh K, Mizushima Y i wsp. Expression of metallothionein-III induced by hypoxia attenuates hypoxia-induced cell death in vitro. Brain Res. 2003; 976: 125-129.
• Thirumoorthy N, Shyam Sunder A, Manisenthil Kumar K, Senthil Kumar M, Ganesh G, Chatterjee M. A review of metallothionein isoforms and their role in pathophysiology. World J Surg Oncol. 2011; 9: 54.
• Vasák M, Hasler DW. Metallothioneins: new functional and structural insights. Curr Opin Chem Biol. 2000; 4: 177-183.
• Quaife CJ, Kelly EJ, Masters BA, Brinster RL, Palmiter RD. Ectopic expression of metallothionein-III causes pancreatic acinar cell necrosis in transgenic mice. Toxicol Appl Pharmacol. 1998; 148: 148-157.
• Sato M, Kondoh M. Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku J Exp Med. 2002; 196: 9-22.
• Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP i wsp. Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia. Biochemistry. 1994;
• 33: 7250-7259.
• Eide DJ. Zinc transporters and the cellular trafficking of zinc. Biochim Biophys Acta. 2006; 1763: 711-722.
• Giles NM, Watts AB, Giles GI, Fry FH, Littlechild JA, Jacob C. Metal and redox modulation of cysteine protein function. Chem Biol. 2003; 10: 677-693.
• Ho E. Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem. 2004; 15: 572-578.
• Bryś M, Nawrocka AD, Miekoś E, Zydek C, Foksiński M, Barecki A, Krajewska WM. Zinc and cadmium analysis in human prostate neoplasms. Biol Trace Elem Res. 1997; 59: 145-152.
• Maret W. Redox biochemistry of mammalian metallothioneins. J Biol Inorg Chem. 2011; 16: 1079-1086.
• Maret W, Jacob C, Vallee BL, Fischer EH. Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc Natl Acad Sci U S A. 1999; 96: 1936-1940.
• Namdarghanbari M, Wobig W, Krezoski S, Tabatabai NM, Petering DH. Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. J Biol Inorg Chem. 2011; 16: 1087-1101.
• Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H i wsp. Cadmium stress: an oxidative challenge. Biometals. 2010; 23: 927-940.
• Pappas RS. Toxic elements in tobacco and in cigarette smoke: inflammation and sensitization. Metallomics. 2011; 3: 1181-1198.
• Fatur T, Tusek M, Falnoga I, Scancar J, Lah TT, Filipic M. DNA damage and metallothionein synthesis in human hepatoma cells (HepG2) exposed to cadmium. Food Chem Toxicol. 2002; 40: 1069-1076.
• Himeno S. Application of metallothionein null cells to investigation of cadmium transport. J Inorg Biochem. 2002; 88: 207-212.
• Mlynek V, Skoczyńska A. Prozapalne działanie kadmu, Postępy Hig. Med. Dośw. 2005; 59: 1–8.
• Stavrides JC. Lung carcinogenesis: pivotal role of metals in tobacco smoke. Free Radic Biol Med. 2006; 41: 1017-1030.
• Templeton DM, Liu Y. Multiple roles of cadmium in cell death and survival. Chem Biol Interact. 2010; 188: 267-275.
• Kakkar P, Jaffery FN. Biological markers for metal toxicity. Environ Toxicol Pharmacol. 2005; 19: 335-349.
• Liu J, Kadiiska MB, Corton JC, Qu W, Waalkes MP, Mason RP i wsp. Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice. Free Radic Biol Med. 2002; 32: 525-535.
• Waalkes MP. Cadmium carcinogenesis in review. J Inorg Biochem. 2000; 79: 241-244.
• Kita K, Miura N, Yoshida M, Yamazaki K, Ohkubo T, Imai Y i wsp. Potential effect on cellular response to cadmium of a single-nucleotide A --> Gpolymorphism in the promoter of the human gene for metallothionein IIA. Hum Genet. 2006; 120: 553-560.
• Lu J, Jin T, Nordberg G, Nordberg M. Metallothionein gene expression in peripheral lymphocytes and renal dysfunction in a population environmentally exposed to cadmium. Toxicol Appl Pharmacol. 2005; 206: 150-156.
• Garrett SH, Phillips V, Somji S, Sens MA, Dutta R, Park S i wsp. Transient induction of metallothionein isoform 3 (MT-3), c-fos, c-jun and c-myc in human proximal tubule cells exposed to cadmium. Toxicol Lett. 2002; 126: 69-80.
• Klaassen CD, Liu J, Diwan BA. Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol. 2009; 238: 215-220.
• Theocharis SE, Margeli AP, Klijanienko JT, Kouraklis GP. Metallothionein expression in human neoplasia. Histopathology. 2004; 45: 103-118.
• Bi Y, Palmiter RD, Wood KM, Ma Q. Induction of metallothionein I by phenolic antioxidants requires metal-activated transcription factor 1 (MTF-1) and zinc. Biochem J. 2004; 380: 695-703.
• Laity JH, Andrews GK. Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys. 2007; 463: 201-210.
• LaRochelle O, Gagné V, Charron J, Soh JW, Séguin C. Phosphorylation is involved in the activation of metal-regulatory transcription factor 1 in response to metal ions. J Biol Chem. 2001; 276: 41879-41888.
• Saydam N, Adams TK, Steiner F, Schaffner W, Freedman JH. Regulation of metallothionein transcription by the metal-responsive transcription factor MTF-1: identification of signal transduction cascades that control metal-inducible transcription. J Biol Chem. 2002; 277: 20438-20445.
• Vasconcelos MH, Tam SC, Hesketh JE, Reid M, Beattie JH. Metal- and tissue-dependent relationship between metallothionein mRNA and protein. Toxicol Appl Pharmacol. 2002; 182: 91-97.
• Wang Y, Wimmer U, Lichtlen P, Inderbitzin D, Stieger B, Meier PJ, Hunziker L, Stallmach T, Forrer R, Rülicke T, Georgiev O, Schaffner W. Metal-responsive transcription factor-1 (MTF-1) is essential for embryonic liver development and heavy metal detoxification in the adult liver. FASEB J. 2004; 18: 1071-1079.
• Günther V, Lindert U, Schaffner W. The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta. 2012; 1823: 1416-1425.
• Chen X, Zhang B, Harmon PM, Schaffner W, Peterson DO, Giedroc DP. A novel cysteine cluster in human metal-responsive transcription factor 1 is required for heavy metal-induced transcriptional activation in vivo. J Biol Chem. 2004; 279: 4515-4522.
• Günes C, Heuchel R, Georgiev O, Müller KH, Lichtlen P, Blüthmann H, Marino S, Aguzzi A, Schaffner W. Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J. 1998; 17: 2846-2854.
• Lichtlen P, Schaffner W. The "metal transcription factor" MTF-1: biological facts and medical implications. Swiss Med Wkly. 2001; 131: 647-652.
• Wimmer U, Wang Y, Georgiev O, Schaffner W. Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione. Nucleic Acids Res. 2005; 33: 5715-5727.
• Rutherford JC, Bird AJ. Metal-responsive transcription factors that regulate iron, zinc, and copper homeostasis in eukaryotic cells. Eukaryot Cell. 2004; 3: 1-13.
• Adams TK, Saydam N, Steiner F, Schaffner W, Freedman JH. Activation of gene expression by metal-responsive signal transduction pathways. Environ Health Perspect. 2002; 110 Suppl 5: 813-817.
• Bourdineaud JP, Baudrimont M, Gonzalez P, Moreau JL. Challenging the model for induction of metallothionein gene expression. Biochimie. 2006;
• 88: 1787-1792.
• Vergani L, Lanza C, Borghi C, Scarabelli L, Panfoli I, Burlando B i wsp. Effects of growth hormone and cadmium on the transcription regulation of two metallothionein isoforms. Mol Cell Endocrinol. 2007; 263: 29-37.
• Thévenod F. Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol. 2009; 238: 221-239.
• Andrews GK. Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol. 2000; 59: 95-104.
• Jiang H, Fu K, Andrews GK. Gene- and cell-type-specific effects of signal transduction cascades on metal-regulated gene transcription appear to be independent of changes in the phosphorylation of metal-response-element-binding transcription factor-1. Biochem J. 2004; 382: 33-41.
• Lau AT, Zhang J, Chiu JF. Acquired tolerance in cadmium-adapted lung epithelial cells: roles of the c-Jun N-terminal kinase signaling pathway and basal level of metallothionein. Toxicol Appl Pharmacol. 2006; 215: 1-8.
• Rao PS, Jaggi M, Smith DJ, Hemstreet GP, Balaji KC. Metallothionein 2A interacts with the kinase domain of PKCmu in prostate cancer. Biochem Biophys Res Commun. 2003; 310: 1032-1038.
• Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012; 24: 981-990.
• Corre S, Galibert MD. USF as a key regulatory element of gene expression. Med Sci (Paris). 2006; 22: 62-67.
• Venugopal R, Jaiswal AK. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H: quinone oxidoreductase1 gene. Proc Natl Acad Sci USA. 1996; 93: 14960-14965
• Ozanne BW, McGarry L, Spence HJ, Johnston I, Winnie J, Meagher L i wsp. Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programme. Eur J Cancer. 2000, 36: 1640-1648.
• Beyersmann D, Hechtenberg S. Cadmium, gene regulation, and cellular signaling in mammalian cells. Toxicol Appl Pharmacol. 1997; 144: 247-261.
• Pathak N, Khandelwal S. Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice. Toxicol Lett. 2007;
• 169: 95-108.
• Bednarek J, Kiliańska ZM.Białka przestrzeni międzybłonowej mitochondriów uczestniczące w procesie apoptozy. Postępy Biochem. 2005; 51: 447–458.
• Kiliańska ZM, Miśkiewicz A. Kaspazy kręgowców: ich rola w przebiegu apoptozy. Postępy Biol Kom. 2003; 30: 129–152.
• Łabędzka K, Grzanka A, Izdebska M. Mitochondrium a śmierć komórki. Postępy Hig Med Dośw. 2006; 60: 439–446.
• Rogalińska M. Alterations in cell nuclei during apoptosis. Cell Mol Biol Lett. 2002; 7: 995-1018.
• Hamada T, Tanimoto A, Sasaguri Y. Apoptosis induced by cadmium. Apoptosis.1997; 2: 359-367
• Pulido MD, Parrish AR. Metal-induced apoptosis: mechanisms. Mutat Res. 2003; 533: 227-241.
• Kim MS, Kim BJ, Woo HN, Kim KW, Kim KB, Kim IK i wsp. Cadmium induces caspase-mediated cell death: suppression by Bcl-2. Toxicology. 2000; 145: 27-37.
• Kondo Y, Rusnak JM, Hoyt DG, Settineri CE, Pitt BR, Lazo JS. Enhanced apoptosis in metallothionein null cells. Mol Pharmacol. 1997; 52: 195-201.
• Aimola P, Carmignani M, Volpe AR, Di Benedetto A, Claudio L, Waalkes MP, van Bokhoven A, Tokar EJ, Claudio PP. Cadmium induces p53-dependent apoptosis in human prostate epithelial cells. PLoS One. 2012; 7: e33647.
• Hengstler JG, Bolm-Audorff U, Faldum A, Janssen K, Reifenrath M, Götte W i wsp. Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. Carcinogenesis. 2003; 24: 63-73.
• Asmuss M, Mullenders LH, Eker A, Hartwig A. Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis. 2000; 21: 2097-2104.
• Witkiewicz-Kucharczyk A, Bal W. Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett. 2006; 162: 29-42.
• Jacob ST, Majumder S, Ghoshal K. Suppression of metallothionein-I/II expression and its probable molecular mechanisms. Environ Health Perspect. 2002; 110 Suppl 5: 827-30.
• Morahan JM, Yu B, Trent RJ, Pamphlett R. Are metallothionein genes silenced in ALS? Toxicol Lett. 2007; 168: 83-87.
• Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000; 36: 1607-1620.
• Edwards JR, Kolman K, Lamar PC, Chandar N, Fay MJ, Prozialeck WC. Effects of cadmium on the sub-cellular localization of β-catenin and β-catenin-regulated gene expression in NRK-52E cells. Biometals. 2012 DOI 10.1007/s10534-012-9592-0
• Chakrabarty S, Radjendirane V, Appelman H, Varani J. Extracellular calcium and calcium sensing receptor function in human colon carcinomas: promotion
• of E-cadherin expression and suppression of beta-catenin/TCF activation. Cancer Res. 2003; 63: 67-71.
• Conacci-Sorrell M, Zhurinsky J, Ben-Ze'ev A. The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest. 2002; 109: 987-991.
• Curran S, Murray GI. Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer. 2000; 36: 1621-1630.
• Heimann R, Hellman S. Individual characterisation of the metastatic capacity of human breast carcinoma. Eur J Cancer. 2000; 36: 1631-1639.
• Beattie JH, Owen HL, Wallace SM, Arthur JR, Kwun IS, Hawksworth GM i wsp. Metallothionein overexpression and resistance to toxic stress. Toxicol Lett. 2005; 157: 69-78.
• Fan LZ, Cherian MG. Potential role of p53 on metallothionein induction in human epithelial breast cancer cells. Br J Cancer. 2002; 87: 1019-1026.
• Méplan C, Richard MJ, Hainaut P. Redox signalling and transition metals
• in the control of the p53 pathway. Biochem Pharmacol. 2000; 59: 25-33.
• Reaves SK, Fanzo JC, Arima K, Wu JY, Wang YR, Lei KY. Expression
• of the p53 tumor suppressor gene is up-regulated by depletion of intracellular zinc in HepG2 cells. J Nutr. 2000; 130: 1688-1694.
• Agarwal ML, Agarwal A, Taylor WR, Stark GR. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest
• in human fibroblasts. Proc Natl Acad Sci USA. 1995; 92: 8493-8497.
• Murphy KL, Rosen JM. Mutant p53 and genomic instability in a transgenic mouse model of breast cancer. Oncogene. 2000; 19: 1045-1051.
• Wani MA, Zhu QZ, El-Mahdy M, Wani AA. Influence of p53 tumor suppressor protein on bias of DNA repair and apoptotic response in human cells. Carcinogenesis. 1999; 20: 765-772.
• Koedrith P, Seo YR. Advances in carcinogenic metal toxicity and potential molecular markers. Int J Mol Sci. 2011; 12: 9576-9595.
• Ostrakhovitch EA, Olsson PE, Jiang S, Cherian MG. Interaction
• of metallothionein with tumor suppressor p53 protein. FEBS Lett. 2006; 580: 1235-1238.
• Lozano G. The oncogenic roles of p53 mutants in mouse models. Curr Opin Genet Dev. 2007; 17: 66-70.
• 115. Elledge RM, Allred DC. Prognostic and predictive value of p53 and p21 in breast cancer. Breast Cancer Res Treat. 1998; 52: 79-98.
• 116. Svechnikova I, Ammerpohl O, Ekström TJ. p21waf1/Cip1 partially mediates apoptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2007; 354: 466-471.
• Thor AD, Liu S, Moore DH 2nd, Shi Q, Edgerton SM. p(21WAF1/CIP1) expression in breast cancers: associations with p53 and outcome. Breast Cancer Res Treat. 2000; 61: 33-43.
• Xie J, Shaikh ZA. Cadmium induces cell cycle arrest in rat kidney epithelial cells in G2/M phase. Toxicology. 2006; 224: 56-65.
• Taylor WR, DePrimo SE, Agarwal A, Agarwal ML, Schönthal AH, Katula KS, Stark GR. Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell. 1999; 10: 3607-3622.
• Jiang H, Fu K, Andrews GK. Gene- and cell-type-specific effects of signal transduction cascades on metal-regulated gene transcription appear to be independent of changes in the phosphorylation of metal-response-element-binding transcription factor-1. Biochem J. 2004; 382: 33-41.
• Fan LZ, Cherian MG. Potential role of p53 on metallothionein induction in human epithelial breast cancer cells. Br J Cancer. 2002; 87: 1019-1026.
• Méplan C, Mann K, Hainaut P. Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem. 1999; 274: 31663-31670.
• Jin R, Chow VT, Tan PH, Dheen ST, Duan W, Bay BH. Metallothionein 2A expression is associated with cell proliferation in breast cancer. Carcinogenesis. 2002; 23: 81-86.
• Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin AS Jr. Selective activation of NF-kappa B subunits in human breast cancer: potential roles
• for NF-kappa B2/p52 and for Bcl-3. Oncogene. 2000; 19: 1123-1131.Doszczak MM, Kaszubowska L, Pierzchalski A, Bigda J. Mechanizm aktywacji czynnika transkrypcyjnego NF-κB przez czynnik martwicy nowotworu (TNF). Postępy Biochem. 2002; 48: 54–65.
• Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW i wsp. Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis. 2000; 21: 871-879.
• Liu P, Kimmoun E, Legrand A, Sauvanet A, Degott C, Lardeux B i wsp. Activation of NF-kappa B, AP-1 and STAT transcription factors is a frequent and early event in human hepatocellular carcinomas. J Hepatol. 2002; 37: 63-71.
• Gruber BM. Czynnik transkrypcyjny NF-κB – nowa perspektywa w leczeniu nowotworów. Postępy Biochem. 2004; 50: 118–130.
• Jin R, Bay BH, Chow VT, Tan PH, Dheen T. Significance of metallothionein expression in breast myoepithelial cells. Cell Tissue Res. 2001; 303: 221-226.
• Jin R, Bay BH, Chow VT, Tan PH. Metallothionein 1F mRNA expression correlates with histological grade in breast carcinoma. Breast Cancer Res Treat. 2001; 66: 265-272.
• Jin R, Bay BH, Chow VT, Tan PH, Lin VC. Metallothionein 1E mRNA is highly expressed in oestrogen receptor-negative human invasive ductal breast cancer. Br J Cancer. 2000; 83: 319-323.
• Barnes NL, Ackland ML, Cornish EJ. Metallothionein isoform expression by breast cancer cells. Int J Biochem Cell Biol. 2000; 32: 895-903.
• Platet N, Cathiard AM, Gleizes M, Garcia M. Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol. 2004; 51: 55-67.
• Osborne CK. Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat. 1998; 51: 227-238.
• Wojnar A, Pula B, Piotrowska A, Jethon A, Kujawa K, Kobierzycki C i wsp. Correlation of intensity of MT-I/II expression with Ki-67 and MCM-2 proteins in invasive ductal breast carcinoma. Anticancer Res. 2011; 31: 3027-3033.
• Gomulkiewicz A, Podhorska-Okolow M, Szulc R, Smorag Z, Wojnar A,
• Zabel M i wsp. Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers. Folia Histochem Cytobiol. 2010; 48: 242-248.
• Krześlak A, Forma E, Jóźwiak P, Szymczyk A, Smolarz B, Romanowicz-Makowska H i wsp. Metallothionein 2A genetic polymorphisms and risk of ductal breast cancer. Clin Exp Med. 2012; DOI 10.1007/s10238-012-0215-4
• Somji S, Garrett SH, Zhou XD, Zheng Y, Sens DA, Sens MA. Absence of Metallothionein 3 Expression in Breast Cancer is a Rare, But Favorable Marker of Outcome that is Under Epigenetic Control. Toxicol Environ Chem. 2010; 92: 1673-1695.

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