Abstract
A review is given of 12 years of research on a human breast epithelial cell line, HMT-3522, which has undergone malignant transformation in vitro without being exposed to known carcinogenic agents. Epigenetic aspects of the malignant transformation have been considered and the results have been viewed in a clinical context. It has been concluded that the history and characteristics of the cell line resembles the comedocarcinoma of the human breast. It is hypothesized that progression from benign lesion to comedo in situ carcinoma and invasive carcinoma occurs if low levels of epidermal growth factor are prevailing in the microenvironment. Our data also suggest that breast cancer developed under high epidermal growth factor receptor activity is estrogen receptor negative, while suppression of epidermal growth factor receptor activity promotes estrogen responsive breast cancer.
References
Prehn RT: Cancers beget mutations versus mutations beget cancers. Cancer Res 54: 5296-5300, 1994
Rhim JS: Neoplastic transformation of human epithelial cells in vitro. Anticancer Res 9: 1345-1366, 1989
Rhim JS, Dritschilo A: Neoplastic transformation in human cell systems-an overview. In: Rhim JS and Dritschilo A (eds) Neoplastic Transformation in Human Cell Culture. The Humana Press, Totowa, NJ, 1991, pp xi-xxxi
Harris CC: Human tissues and cells in carcinogenesis research. Cancer Res 47: 1-10, 1987
Chang SE, Keen J, Lane EB, Taylor-Papadimitriou J: Establishment and characterization of SV40-transformed human breast epithelial cell lines. Cancer Res 42: 2040-2053, 1982
Rudland PS, Ollerhead G, Barraclough R: Isolation of simian virus 40-transformed human mammary epithelial stem cell lines that can differentiate to myoepithelial-like cells in culture and in vivo. Dev Biol 136: 167-180, 1989
Band V, Zajchowski D, Kulesa V, Sager R: Human papilloma virus DNA2 immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Natl Acad Sci USA 87: 463-467, 1990
Stampfer MR, Bartley JC: Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo(a)pyrene. Proc Natl Acad Sci USA 82: 2394-2398, 1985
Gollahon LS, Shay JW: Immortalization of human mammary epithelial cells transfected with mutant p53 (273(his)). Oncogene 12: 715-725, 1996
Gao QS, Hauser SH, Liu XL, Wazer DE, MadocJones H, Band V: Mutant p53-induced immortalization of primary human mammary epithelial cells. Cancer Res 56: 3129-3133, 1996
Kiyono T, Foster SA, Koop J, McDougall JK, Galloway DA, Klingelhutz AJ: Both Rb/p16ink4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396: 84-88, 1998
Shay JW, Tomlinson G, Piatyszek MA, Gollahon LS: Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol Cell Biol 15: 425-432, 1995
Clark R, Stampfer MR, Milley R, O'Rourke E, Walen KH, Kriegler M, Kopplin J, McCormick F: Transformation of human mammary epithelial cells by oncogenic retroviruses. Cancer Res 48: 4689-4694, 1988
Kao CY, Oakley CS, Welsch CW, Chang CC: Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty. In vitro Cell Dev Biol Animal 33: 282-288, 1997
Kang KS, Sun W, Nomata K, Morita I, Cruz A, Liu CJ, Trosko JE, Chang CC: Involvement of tyrosine phosphorylation of p185c-erbB2/neu in tumorigenicity induced by X-rays and the neu oncogene in human breast epithelial cells. Mol Carcinogen 21: 225-233, 1998
Polanowski FP, Gaffney EV, Burke RE: HBL-100, a cell line established from human breast milk. In vitro 12: 328-328, 1976
Caron de Fromentel C, Nardeux PC, Soussi T, Lavialle C, Estrade S, Carloni G, Chandrasekaran K, Cassingena R: Epithelial HBL-100 cell line derived from milk of an apparently healthy woman harbours SV40 genetic information. Exp Cell Res 160: 83-94, 1985
Berthon P, Goubin G, Dutrillaux B, Degeorges A, Faille A, Gespach C, Calvo F: Single-step transformation of human breast epithelial cells by SV40 large T oncogene. Int J Cancer 52: 92-97, 1992
Wazer DE, Chu Q, Liu X-L, Gao Q, Safaii H, Band V: Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol Cell Biol 14: 2468-2478, 1994
Briand P, Petersen OW, van Deurs B: A new diploid nontumorigenic human breast epithelial cell line isolated and propagated in chemically defined medium. In vitro Cell Dev Biol 23: 181-188, 1987
Soule HD, Maloney TM, Wolman SR, Peterson WD jr., Brenz R, McGrath CM, Russo J, Pauley RJ, Jones RF, Brooks SC: Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 50: 6075-6086, 1990
Barnabas N, Moraes R, Calaf G, Estrada S, Russo J: Role of p53 in MCF-10F cell immortalization and chemically-induced neoplastic transformation. Int J Oncol 7: 1289-1296, 1995
Calaf G, Russo J: Transformation of human breast epithelial cells by chemical carcinogens. Carcinogenesis 14: 483-492, 1993
Briand P, Nielsen KV, Madsen MW, Petersen OW: Trisomy 7p and malignant transformation of human breast epithelial cells following EGF withdrawal. Cancer Res 56: 2039-2044, 1996
Rubin H: Experimental control of neoplastic progression in cell populations: Foulds' rules revisited. Proc Natl Acad Sci USA 91: 6619-6623, 1994
Rubin H: Epigenetic nature of neoplastic transformation. In: Hodges GM, Rowlatt C (eds) Developmental Biology and Cancer, CRC Press, Boca Raton, 1994, pp 61-84
Nielsen KV, Briand P: Cytogenetic analysis of in vitro karyotype evolution in a cell line established non-malignant human mammary epithelium. Cancer Genet Cytogenet 39: 103-118, 1989
Madsen MW, Lykkesfeldt AE, Laursen I, Nielsen KV, Briand, P: Altered gene expression of c-myc, epidermal growth factor receptor, transforming growth factor-, and c-erb-B2 in an immortalized breast epithelial cell line, HMT-3522, is associated with decreased growth factor requirements. Cancer Res 52: 1210-1217, 1992
Moyret C, Madsen MW, Cooke J, Briand P, Theillet C: Gradual selection of a cellular clone presenting a mutation at codon 179 of the p53 gene during establishment of the immortalized human breast epithelial cell line, HMT-3522. Exp Cell Res 215: 380-385, 1994
Nielsen KV, Madsen MW, Briand P: In vitro karyotype evolution and cytogenetic instability in the non-tumorigenic human breast epithelial cell line, HMT-3522. Cancer Genet Cytogenet 78: 189-199, 1994
Weaver VM, Howlett AR, Langtonwebster B, Petersen OW, Bissel MJ: The development of a functionally relevant cell culture model of progressive human breast cancer. Semin Cancer Biol 6: 175-184, 1995
Lundholt BK, Madsen MW, Lykkesfeldt AE, Petersen OW, Briand P: Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor (ER) cDNA. Mol Cell Endocrinol 119: 47-59, 1996
Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, Bissell MJ: Reversion of the malignant phenotype of human breast cells in 3-dimensional culture and in vivo using integrin blocking antibodies. J Cell Biol 137: 231-246, 1997
Nielsen KV, Niebuhr E, Ejlertsen B, Holstebroe S, Madsen MW, Briand P, Mouridsen HT, Bolund L: Molecular cytogenetic analysis of a nontumorigenic human breast epithelial cell line that eventually turns tumorigenic-Validation of an analytical approach combining karyotyping, comparative genomic hybridization, chromosome painting, and single locus FISH. Genes Chromosom Cancer 20: 30-37, 1997
Villadsen R, Nielsen KV, Bolund L, Briand P: Complete loss of wild type TP53 in a non-transformed human epithelial cell line is preceded by a phase during which a heterozygous TP53 mutant effectively outgrows the homozygous wild type cells. Cancer Genet Cytogenet 116: 28-34, 2000
Wang F, Weaver VM, Petersen OW, Larabell CA, Dedhar S, Briand P, Lupu R, Bissell MJ: Reciprocal interactions between 1-integrin and epidermal growth factor receptor in three dimensional basement membrane breast cultures: A different perspective in epithelial biology. Proc Natl Acad Sci USA 95: 14821-14826, 1998
Vlatkovic L, Lykkesfeldt AE, Hou-Jensen K, Briand P: Comparison of the immunocytochemical assay (ER-ICA) and the biochemical assay for estrogen receptor in human breast cancer cell lines. Eur J Cancer Clin Oncol 23: 755-760, 1987
Petersen OW, Hansen SH, Laursen I, van Deurs B: Effect of insulin on growth and expression of smooth muscle isoactin in human breast gland myoepithelial cells in a chemically defined culture system. Eur J Cell Biol 50: 500-509, 1989
McAndrew J, Fernig DG, Rudland PS, Smith JA: Secretion of transforming growth factor alpha and expression of its receptor in mammary cell lines. Growth Factors 10: 281-287, 1994
Briand P, Lundholt BK, Skouv J, Lykkesfeldt AE: Growth response of breast epithelial cells to estrogen is influenced by EGF. Mol Cell Endocrinol 153: 1-9, 1999
Lundholt BK, Larsen SS, Lykkesfeldt AE, Briand P: Attempts to clarify estradiol-mediated growth inhibition of the estrogen receptor transfected nontumorigenic human breast epithelial cell line, HMT-3522/F9. Keystone Symposium, USA, Nuclear receptor gene family, 1998 (Abstract)
Petersen OW, Rønnov-Jessen L, Howlett AR, Bissell MJ: Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci USA 89: 9064-9068, 1992
Rønnov-Jessen L, Petersen OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: The importance of the stromal reaction. Physiol Rev 76: 69-125, 1996
Balslev I, Christensen IJ, Rasmussen BB, Larsen JK, Lykkesfeldt AE, Thorpe SM, Rose C, Briand P, Mouridsen HT: Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer. Int J Cancer 56: 16-25, 1994
Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: The Richard and Linda Rosenthal Foundation Award Lecture. Cancer Res 48: 246-253, 1988
King RJB: Estrogen and progestin effect in human breast carcinogenesis. Breast Cancer Res Treat 27: 3-15, 1993
Levenson AS, Jordan VC: Transfection of human estrogen receptor (ER) cDNA into ER-negative mammalian cell lines. J Steroid Biochem Mol Biol 51: 229-239, 1994
Hannink M, Temin HM: Cancer as a mutation-driven evolutionary process. In: Paukovits WR (ed) Growth Regulation and Carcinogenesis, Vol. 1, CRC Press, Boca Raton, Florida, 1991, pp 95-97
Wazer DE, Liu XL, Chu QM, Gao QS, Band V: Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7. Proc Natl Acad Sci USA 92: 3687-3691, 1995
Sun W, Kang KS, Morita I, Trosko JE, Chang CC: High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization. Cancer Res 59: 6118-6123, 1999
Schehr RS: Rethinking the development of breast cancer. Nat Biotechnol 15: 517-518, 1997
Johansson B, Heim S, Mandahl N, Mertens F, Mitelman F: Trisomy 7 in nonneoplastic cells. Genes Chromosom Cancer 6: 199-205, 1993
Gullick WJ, Srinivasan R: The type 1 growth factor receptor family: new ligands and receptors and their role in breast cancer. Breast Cancer Res Treat 52: 43-53, 1998.
Larsen SS, Egeblad M, Jäättelä M, Lykkesfeldt AE: Acquired antiestrogen resistance in MCF-7 human breast cancer sublines is not accomplished by altered expression of receptors in the ErbB-family. Breast Cancer Res Treat 1524: 41-56, 1999
Patchefsky AS, Schwartz GF, Finkelstein SD, Prestipino A, Sohn SE, Singer JS, Feig SA: Heterogeneity of intraductal carcinoma of the breast. Cancer 63: 731-741, 1989
Steeg PS, Clare SE, Lawrence JA, Zhou Q: Molecular analysis of premalignant and carcinoma in situ lesions of the human breast. Am J Pathol 149: 733-738, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Briand, P., Lykkesfeldt, A.E. An in vitro Model of Human Breast Carcinogenesis: Epigenetic Aspects. Breast Cancer Res Treat 65, 179–187 (2001). https://doi.org/10.1023/A:1006434503061
Issue Date:
DOI: https://doi.org/10.1023/A:1006434503061