Abstract
Metallothioneins (MTs) are ubiquitous low-molecular-weight proteins with a high affinity for heavy metal ions such as zinc, copper and cadmium. MT over-expression has been associated with resistance against anticancer drugs. In the present study we investigated 86 cases (45 cases of tumour category pT1 and 41 of category pT2) of routinely fixed and paraffin-embedded primary breast carcinomas immunohistochemically with a monoclonal antibody to an epitope of MT shared by its I and II isoforms. Immunohistochemically demonstrated MT over-expression was found in the invasive components of 7 of 32 pT1 and 17 of 28 pT2 invasive ductal carcinomas, whereas all 26 invasive lobular carcinomas gave weak or negative results. Fourteen of 17 pT2 and 2 of 7 pT1 invasive ductal carcinomas with MT over-expression developed metastases during follow-up with poor prognostic outcome. In contrast only 3 of 11 pT2 and none of the 25 pT1 cases without MT over-expression had a poor clinical course (P < 0.001). It is concluded that MT over-expression is associated with significantly poor prognosis particularly in pT2 invasive ductal breast carcinomas.
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Andrew SM, Jasani B (1987) An improved method for the inhibition of endogenous peroxidase non-deleterious to lymphocyte surface markers. Application to immunoperoxidase studies on eosinophil-rich tissue preparations. Histochem J 19:426–430
Andrews PA, Murphy MP, Howell SB (1987) Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19:149–154
Beck WT, Müller TJ, Tanzer LR (1979) Altered surface membrane glycoproteins in vinca alkaloid-resistance human leukemic lymphoblasts. Cancer Res 39:2070–2075
Elmes ME, Clarkson JP, Mahy NJ, Jasani B (1989) Metallothionein and copper in liver disease with copper retention: a histopathological study. J Pathol 158:131–137
E.O.R.T.C. (1980) Breast cancer cooperative group. Revision of the standards for the assessment of hormone receptors in human breast cancer. Eur J Cancer 16:1513–1515
Evering WE, Haywood S, Elmes ME, Jasani B, Trafford J (1990) Histochemical and immunohistochemical evalation of copper and metallothionein in the liver and kidney of copper-loaded rats. J Pathol 160:305–312
Frei E III, Cucchi CA, Rosowsky A, Tantravahi R, Bernal S, Ervin TJ, Ruprecht RM, Haseltine WA (1985) Alkylating agent resistance: in vitro studies with human cell lines. Proc Natl Acad Sci USA 82:2158–2162
Friberg L, Piscator M, Nordberg GR, Kjellström T (1974) Cadmium in the environment, 2nd edn. CRC Press, Boca Raton
Fuller CE, Elmes ME, Jasani B (1990) Age-related changes in metallothionein, copper, copper-associated protein, and lipofuscin in human liver: a histochemical and immunohistochemical study. J Pathol 161:167–172
Goering PL, Klaassen CD (1984) Zinc-induced tolerance to cadmium hepatoxicity. Toxicol Appl Pharmacol 74:299–307
Hamer DH (1986) Metallothionein. Annu Rev Biochem 55:913–951
Hittmair A, Schmid KW (1989) Inhibition of endogenous peroxidase for the immunohistochemical demonstration of intermediate filament proteins (IFP). Immunol Methods 116:199–205
Jasani B, Elmes ME (1991) Immunohistochemical detection of metallothionein. Methods Enzymol 205:95–107
Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem Biophys Acta 455:152–162
Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. Wiley, New York
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Karasawa M, Hosoi J, Hashiba H, Nose K, Tohyama C, Abe E, Suda T, Kuroki T (1987) Regulation of metallothionein gene expression by 1-alpha, 25-dihydroxyvitamin D3 in cultured cells and in mice. Proc Natl Acad Sci USA 84:8810–8814
Kartner N, Riordan JR, Ling V (1983) Cell surface P-glycoprotein assosiated with multidrug resistance in mammalian cell lines. Science 221:1285–1288
Kelley SM, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS (1988) Overexpression of metallotheionein confers resistance to anticancer drugs. Science 241:1813–1815
Leber AP, Miya T (1976) A mechanism for Cd and Zn induced tolerance to cadmium toxicity: involvement of metallothionein. Toxicol Appl Pharmacol 37:403–414
Moscow JA, Townsend AJ, Goldsmith E, Whang-Peng J, Vickers PJ, Poisson R, Legault-Poisson S, Myers CE, Cowan KH (1988) Isolation of the human anionic glutathione S-transferase cDNA and the relationship of its gene expression to estrogen-receptor content in primary breast cancer. Proc Natl Acad Sci USA 85:6518–6522
Nartey N, Cherigan MG, Banerjee D (1987) Immunohistochemical localization of metallothionein in human thyroid tumors. Am J Pathol 129:177–182
Nath R, Kambadur R, Gulati S, Paliwal VK, Sharma M (1988) Molecular aspects, physiological functions, and clinical significance of metallothioneins. Crit Rev Food Sci Nutr 27:41–85
Nomiyama K, Nomiyama H, Akahori F, Masaoka T (1982) Cadmium health effects in monkeys with special reference to the critical concentration of Cd in the renal cortex. In: Cadmium 81, Proceedings of the 3rd International Cadmium Conference, Miami, p 151
Peterson RHF, Meyers MB, Spengler BA, Biedler JL (1983) Alterations of plasma membrane glycopeptides and gangliosides of Chinese hamster cells accompanying development of resistance to daunorubicin and vincristine. Cancer Res 43:222–228
Reid A, Pereira H, Galea M, Bell JA, Elston CW, Jasani B, Schmid KW, Kay J, Cryer A, Blamey RW, Ellis IO (1992) Metallothionein in human breast cancer. J Pathol [Suppl] 167:29A
Scanlon KJ, Kashani-Sabet M (1985) Elevated expression of thymidylate synthase cycle genes in cisplatin-resistant human ovarian carcinoma A2780 cells. Proc Natl Acad Sci USA 85:650–653
Schmid KW, Hittmair A, Tauscher T, Dünser M, Tötsch M, Öfner D, Jasani B (1990) Metallothionein-Expression in Mammakarzinomen — Zusammenhang mit Zytostatikaresistenz, Östrogenrezeptorstatus und Prognose. Verh Dtsch Ges Pathol 74:598
Slater EP, Cato ACB, Karin M, Baxter JD, Beato M (1988) Progesterone induction of metallothionein-IIA gene expression. Mol Endocrinol 2:485–491
Spiessl B, Beahrs OH, Hermanek P, Hutter RVP, Scheibe O, Sobin LH, Wagner G (1989) Breast tumours. In: TNM atlas. Illustrated guide to the TNM/pTNM-classification of malignant tumours. Springer, Berlin Heidelberg New York, pp 173–183
Teicher BA, Cucchi CA, Lee JB, Flatow JL, Rosowsky A, Frei E III (1986) Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. Cancer Res 46:4379–4383
Teicher BA, Holden SA, Kelley MJ, Shea TC, Cucchi CA, Rosowsky A, Henner WD, Frei E III (1987) Characterization of a human squamous carcinoma cell line resistant to cis-diaminedichloroplatinum (II). Cancer Res 47:388–293
Thornalley PJ, Vasak M (1985) Possible role of metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with Superoxide and hydroxyl radicals. Biochem Biophys Acta 827:36–44
Vickers PJ, Dickson RB, Shoemaker R, Cowan KH (1988) A multidrug resistant human breast cancer line which exhibits crossresistance to anti-oestrogen and hormone-independent tumour growth in vivo. Mol Endocrinol 2:886–892
Webber MM, Rehman SMM, James GT (1988) Metallothionein induction and deinduction in human prostatic carcinoma cells: relationship with resistance and sensitivity to adriamycin. Cancer Res 48:4503
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Schmid, K.W., Ellis, I.O., Gee, J.M.W. et al. Presence and possible significance of immunocytochemically demonstrable metallothionein over-expression in primary invasive ductal carcinoma of the breast. Vichows Archiv A Pathol Anat 422, 153–159 (1993). https://doi.org/10.1007/BF01607167
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DOI: https://doi.org/10.1007/BF01607167