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Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions

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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.

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References

  1. Bussolati G, Botta G, Gugliotta P: Actin-rich (myoepithelial) cells in ductal carcinomain situ of the breast. Virchows Arch B 34: 251–259, 1980

    Google Scholar 

  2. 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

    Google Scholar 

  3. 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

    Google Scholar 

  4. 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

    Google Scholar 

  5. Russo J, Russo IH: Immunocytochemical markers in breast cancer. In: DeLellis (ed) Adv Immunohistochem, Raven Press, New York, pp 431–466, 1988

    Google Scholar 

  6. 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

    Google Scholar 

  7. 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

    Google Scholar 

  8. 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

    Google Scholar 

  9. Kägi JHR: Overview of metallothionein. Methods in Enzymol 205: 613–626, 1991

    Google Scholar 

  10. 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

    Google Scholar 

  11. 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

  12. 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

    Google Scholar 

  13. 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

    Google Scholar 

  14. 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

    Google Scholar 

  15. 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

    Google Scholar 

  16. 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

    Google Scholar 

  17. 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

    Google Scholar 

  18. 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

    Google Scholar 

  19. 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

    Google Scholar 

  20. 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

    Google Scholar 

  21. Azzopardi JG: Problems in Breast Pathology. W.B. Saunders Company, London, 1979

    Google Scholar 

  22. Haagensen CD, Bodian C, Haagensen DE Jr: Breast carcinoma. Risk and detection. W.B. Saunders, Philadelphia, 1981

    Google Scholar 

  23. Page DL, Anderson TJ: Diagnostic Histopathology of the Breast. Churchill Livingstone, Edingburgh, 1987

    Google Scholar 

  24. Carter D: Interpretation of breast biopsies. Raven Press, New York, 1990

    Google Scholar 

  25. Fechner RE: Ductal carcinoma involving the lobule of the breast. A source of confusion with lobular carcinomain situ. Cancer 28: 274–281, 1971

    Google Scholar 

  26. Fechner RE, Mills SE: Breast pathology. Benign proliferations, atypias andin situ carcinomas. ASCP Press, Chicago, 1990

    Google Scholar 

  27. 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

    Google Scholar 

  28. 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

    Google Scholar 

  29. 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

    Google Scholar 

  30. Jasani B, Elmes ME: Immunohistochemical detection of metallothionein. Methods in Enzymology 205: 95–107, 1991

    Google Scholar 

  31. Eusebi V, Magelhaes F, Azzopardi JGL: Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol 23: 655–662, 1992

    Google Scholar 

  32. Weidner N, Semple JP: Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol 23: 1167–1171, 1992

    Google Scholar 

  33. Hamer DH: Metallothionein. Ann Rev Biochem 55: 913–951, 1986

    Google Scholar 

  34. 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

    Google Scholar 

  35. Slater EP, Cato ACB, Karin M, Baxter JD, Beato M: Progesterone induction of metallothionein-IIA gene expression. Mol Endocrinol 2: 485–491, 1988

    Google Scholar 

  36. Friedberg L, Piscator M, Nordberg GR, Kjellström T: Cadmium in the environment. 2nd Edition, CRC Press, Boca Raton, 1974

    Google Scholar 

  37. Goering PL, Klaassen CD: Zinc-induced tolerance to cadmium hepatoxicity. Toxicol Appl Pharmacol 74: 299–307, 1984

    Google Scholar 

  38. Andrews PA, Murphy MP, Howell SB: Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19: 149–154, 1987

    Google Scholar 

  39. 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

    Google Scholar 

  40. 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

    Google Scholar 

  41. Raju U, Crissman JD, Zarbo RL, Gottlieb C: Epitheliosis of the breast. Am J Surg Pathol 14: 939–947, 1990

    Google Scholar 

  42. 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

    Google Scholar 

  43. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  44. Udom AO, Brady FO: Reactivationin vitro of zinc-requiring apo-enzymes by rat liver zinc-thionein. Biochem J 187: 329–335, 1980

    Google Scholar 

  45. Murphy G, Reynolds JJ, Hembry RM: Metalloproteinases in cancer invasion and metastases. Int J Cancer 44: 757–760, 1989

    Google Scholar 

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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

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