Abstract
Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypicallobular hyperplasia, lobular carcinomain situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductalin situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression.In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.
References
Bussolati G, Botta G, Gugliotta P: Actin-rich (myoepithelial) cells in ductal carcinomain situ of the breast. Virchows Arch B 34: 251–259, 1980
Nagle RB, Böcker W, Davis JR, Heid HW, Kaufmann M, Lucas DO, Jarasch E-D: Characterization of breast carcinomas by two monoclonal antibodies distinguishing myoepithelial from luminal epithelial cells. J Histochem Cytochem 34: 869–881, 1986
Böcker W, Jarasch E-D, Nagle RB, Höhne R: Morphology, topography, and pattern of benign epithelial proliferations and pre-invasive carcinoma. In: Bässler R, Hübner K (eds) Pathology of Neoplastic and Endocrine Induced Diseases of the Breast. Gustav Fischer, Stuttgart, pp 72–86, 1986
Jarasch E-D, Nagle RB, Kaufmann M, Maurer C, Böcker W: Differential diagnosis of benign epithelial proliferations and carcinomas of the breast using antibodies to cytokeratins. Hum Pathol 18: 276–289, 1988
Russo J, Russo IH: Immunocytochemical markers in breast cancer. In: DeLellis (ed) Adv Immunohistochem, Raven Press, New York, pp 431–466, 1988
Böcker W, Bier B, Freytag G, Brömmelkamp B, Jarasch E-D, Edel G, Dockhorn-Dworniczak B, Schmid KW: An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part I: normal breast and benign proliferative lesions. Virchows Archiv A 421: 315–322, 1992
Böcker W, Bier B, Freytag G, Brömmelkamp B, Jarasch E-D, Edel G, Dockhorn-Dworniczak B, Schmid KW: An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part II: epitheliosis and ductal carcinomain situ. Virchows Arch A 421: 323–330, 1992
Nath R, Kambadur R, Gulati S, Paliwal VK, Sharma M: Molecular aspects, physiological functions, and clinical significance of metallothioneins. Critical Rev Food Sci Nutr 27: 41–85, 1988
Kägi JHR: Overview of metallothionein. Methods in Enzymol 205: 613–626, 1991
Leber AP, Miya T: A mechanism for Cd and Zn induced tolerance to cadmium toxicity: involvement of metallothionein. Toxicol Appl Pharmacol 37: 403–414, 1976
Nomiyama K, Nomiyama H, Akahori F, Masaoka T: Cadmium health effects in monkeys with special reference to the critical concentration of Cd in the renal cortex. In: Cadmiun 81, Proc 3rd Int Cadmium Conf, Miami, p 151, 1982
Thornalley PJ, Vasak M: 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, 1985
Schmid KW, Hittmair A, Tauscher T, Dünser M, Tötsch M, Öfner D, Jasani B: Metallothionein-Expression in Mamma-karzinomen- Zusammenhang mit Zytostatikaresistenz, Östrogenrezeptorstatus und Prognose. Verh Dtsch Ges Pathol74: 598, 1990
Reid A, Pereira H, Galea M, Bell JA, Elston CW, Jasani B, Schmid KW, Kay J, Cryer A, Blamey RW, Ellis IO: Metal-lothionein in human breast cancer. J Pathol suppl 167: 29A, 1992
Schmid KW, Ellis IO, Gee JMW, Darker BM, Lees WE, Kay J, Cryer A, Stark A, Hittmair A, Öfner D, Dünser M, Margreiter R, Daxenbichler G, Nicholson RI, Bier B, Böcker W, Jasani B: Presence and possible significance of immunocytochemically demonstrable metallothionein over-expression in primary invasive ductal carcinoma of the breast. Virchows Archiv A 422: 153–159, 1993
Zelger B, Schir M, Hittmair A, Öfner C, Fritsch P, Jasani B, Schmid KW: Metallothionein over-expression in malignant melanoma - a prognostically useful factor? J Cut Pathol 18: 398, 1991
Zelger B, Schir M, Hittmair A, Öfner C, Fritsch P, Jasani B, Schmid KW: Metallothionein over-expression in malignant melanoma - a factor of prognostic value? Arch Dermatol Res 284: 56, 1992
Zelger B, Hittmair A, Schir M, Öfner C, Öfner D, Fritsch PO, Böcker W, Jasani B, Schmid KW: Immunohistochemically demonstrated metallothionein expression in malignant melanoma. Histopathology 23: 257–264, 1993
Schmid KW, Zelger B, Hittmair A, Laidler P, Jasani B, Böcker W: Metallothionein-Überexpression in malignen Melanomen. Zusammenhang mit Prognose und Therapie. Verh Dtsch Ges Pathol 76: 512, 1992
Shukla VK, Laidler P, Schmid KW, Zelger B, Horgan K, Hughes LE, Elmes ME, Jasani B: Metallothionein as a discriminant marker in thin melanoma. J Pathol 169: 177, 1993
Azzopardi JG: Problems in Breast Pathology. W.B. Saunders Company, London, 1979
Haagensen CD, Bodian C, Haagensen DE Jr: Breast carcinoma. Risk and detection. W.B. Saunders, Philadelphia, 1981
Page DL, Anderson TJ: Diagnostic Histopathology of the Breast. Churchill Livingstone, Edingburgh, 1987
Carter D: Interpretation of breast biopsies. Raven Press, New York, 1990
Fechner RE: Ductal carcinoma involving the lobule of the breast. A source of confusion with lobular carcinomain situ. Cancer 28: 274–281, 1971
Fechner RE, Mills SE: Breast pathology. Benign proliferations, atypias andin situ carcinomas. ASCP Press, Chicago, 1990
Elmes ME, Clarkson JP, Mahy NJ, Jasani B: Metallothionein and copper in liver disease with copper retention - a histopathological study. J Pathol 158: 131–137, 1989
Evering WE, Haywood S, Elmes ME, Jasani B, Trafford J: Histochemical and immunohistochemical evaluation of copper and metallothionein in the liver and kidney of copper-loaded rats. J Pathol 160: 305–312, 1990
Fuller CE, Elmes ME, Jasani B: Age-related changes in metallothionein, copper, copper-associated protein, and lipofuscin in human liver: a histochemical and immunohistochemical study. J Pathol 161: 167–172, 1990
Jasani B, Elmes ME: Immunohistochemical detection of metallothionein. Methods in Enzymology 205: 95–107, 1991
Eusebi V, Magelhaes F, Azzopardi JGL: Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol 23: 655–662, 1992
Weidner N, Semple JP: Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol 23: 1167–1171, 1992
Hamer DH: Metallothionein. Ann Rev Biochem 55: 913–951, 1986
Karasawa M, Hosei J, Hashiba H, Nose K, Tohyama C, Abe E, Suda T, Kuroki T: 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, 1987
Slater EP, Cato ACB, Karin M, Baxter JD, Beato M: Progesterone induction of metallothionein-IIA gene expression. Mol Endocrinol 2: 485–491, 1988
Friedberg L, Piscator M, Nordberg GR, Kjellström T: Cadmium in the environment. 2nd Edition, CRC Press, Boca Raton, 1974
Goering PL, Klaassen CD: Zinc-induced tolerance to cadmium hepatoxicity. Toxicol Appl Pharmacol 74: 299–307, 1984
Andrews PA, Murphy MP, Howell SB: Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19: 149–154, 1987
Webber MM, Regman SMM, James GT: Metallothionein induction and deinduction in human prostatic carcinoma cells: relationship with resistance and sensitivity to adriamycin. Cancer Res 48: 4503–4508, 1988
Kelley SM, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS: Overexpression of metallotheionein confers resistance to anticancer drugs. Science 241: 1813–1815, 1988
Raju U, Crissman JD, Zarbo RL, Gottlieb C: Epitheliosis of the breast. Am J Surg Pathol 14: 939–947, 1990
Purkis RE, Steel JW, MacKenzie JC, Nathrath WB, Leigh IM, Lane EB: Antibody markers of basal cells in complex epithelia. J Cell Science 97: 39–50, 1990
Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991
Udom AO, Brady FO: Reactivationin vitro of zinc-requiring apo-enzymes by rat liver zinc-thionein. Biochem J 187: 329–335, 1980
Murphy G, Reynolds JJ, Hembry RM: Metalloproteinases in cancer invasion and metastases. Int J Cancer 44: 757–760, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bier, B., Douglas-Jones, A., Tötsch, M. et al. Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions. Breast Cancer Res Tr 30, 213–221 (1994). https://doi.org/10.1007/BF00665963
Issue Date:
DOI: https://doi.org/10.1007/BF00665963