This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Briand, P. Articles by Petersen, O. W. Search for Related Content PubMed PubMed Citation Articles by Briand, P. Articles by Petersen, O. W.

Trisomy 7p and Malignant Transformation of Human Breast Epithelial Cells following Epidermal Growth Factor Withdrawal¹

Department of Tumor Endocrinology, Division for Cancer Biology, The Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark [P. B., M. W. M.]; Department of Medical Genetics, Institute of Medical Biochemistry and Genetics [K. V. N.], and Structural Cell Biology Unit, Department of Anatomy, Section A [O. W. P.], The Panum Institute, University of Copenhagen, Denmark

We have reported previously on the first spontaneously immortalized, nonmalignant human breast epithelial cell line, HMT-3522, which is entirely dependent on exogenous epidermal growth factor (EGF). In passage 118, cells were adapted to grow in medium without EGF and a new growth-transformed subline, HMT-3522/gt-1, was generated and propagated at high growth rate without exogenous EGF (Madsen et al., Cancer Res., 52: 1210–1217, 1992). Here we have used this subline and the continuum of the parent line, HMT-3522/wt, to pose the question whether a relevant change in a physiological parameter of the microenvironment will induce malignant transformation. The two cell lines were cultured under identical conditions with the only exception that EGF was omitted in the medium for gt-1. Initially, wt and gt-1 were identical in terms of karyotype as well as morphology, growth rate, and protein expression as revealed by two-dimensional gel electrophoresis. A highly dramatic shift in phenotype was observed in passage 238 when the gt-1 line became tumorigenic in nude mice. After two mouse-culture passages, the resulting malignantly transformed cell line (HMT-3522/mt-1) was refractory to the growth-modulating effect of EGF and presented an extra copy of a chromosome marker, 7q-, as the only cytogenetic difference from the gt-1. Our results suggest that microenvironmental cues are powerful factors in the induction of malignancy. A major role of EGF receptor in the malignant transformation is emphasized by loss of EGF sensitivity and acquisition of an extra chromosome 7p harboring the EGF receptor gene. We hypothesize that during premalignant hyperplasia, a population of EGF/transforming growth factor autonomous epithelial cells in situ may develop as a consequence of local transforming growth factor deprivation, a condition reflected in the culture model as autonomy after EGF withdrawal.

¹ This work was supported by the Danish Cancer Society, the Gangsted Foundation, the Haensch Foundation, the Novo-Nordic Foundation, the Mrs. Astrid Thaysen Foundation, the Velux Foundation, the Else and Mogens Wedell-Wedellsborg Foundation, the Willumsen Foundation, and the Birthe and John Meyer Foundation.

² To whom requests for reprints should be addressed.

Received 11/17/95. Accepted 3/ 4/96.

This article has been cited by other articles:

				A. Rizki, V. M. Weaver, S.-Y. Lee, G. I. Rozenberg, K. Chin, C. A. Myers, J. L. Bascom, J. D. Mott, J. R. Semeiks, L. R. Grate, et al. A Human Breast Cell Model of Preinvasive to Invasive Transition Cancer Res., March 1, 2008; 68(5): 1378 - 1387. [Abstract] [Full Text] [PDF]

				A. Rizki, J. D. Mott, and M. J. Bissell Polo-like Kinase 1 Is Involved in Invasion through Extracellular Matrix Cancer Res., December 1, 2007; 67(23): 11106 - 11110. [Abstract] [Full Text] [PDF]

				G. Chandramouly, P. C. Abad, D. W. Knowles, and S. A. Lelievre The control of tissue architecture over nuclear organization is crucial for epithelial cell fate J. Cell Sci., May 1, 2007; 120(9): 1596 - 1606. [Abstract] [Full Text] [PDF]

				T. Sandal, K. Valyi-Nagy, V. A. Spencer, R. Folberg, M. J. Bissell, and A. J. Maniotis Epigenetic Reversion of Breast Carcinoma Phenotype Is Accompanied by Changes in DNA Sequestration as Measured by AluI Restriction Enzyme Am. J. Pathol., May 1, 2007; 170(5): 1739 - 1749. [Abstract] [Full Text] [PDF]

				D. W. Knowles, D. Sudar, C. Bator-Kelly, M. J. Bissell, and S. A. Lelievre Automated local bright feature image analysis of nuclear protein distribution identifies changes in tissue phenotype PNAS, March 21, 2006; 103(12): 4445 - 4450. [Abstract] [Full Text] [PDF]

				H. Liu, D. C. Radisky, C. M. Nelson, H. Zhang, J. E. Fata, R. A. Roth, and M. J. Bissell Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. PNAS, March 14, 2006; 103(11): 4134 - 4139. [Abstract] [Full Text] [PDF]

				A. J. Maniotis, K. Valyi-Nagy, J. Karavitis, J. Moses, V. Boddipali, Y. Wang, R. Nunez, S. Setty, Z. Arbieva, M. J. Bissell, et al. Chromatin Organization Measured by AluI Restriction Enzyme Changes with Malignancy and Is Regulated by the Extracellular Matrix and the Cytoskeleton Am. J. Pathol., April 1, 2005; 166(4): 1187 - 1203. [Abstract] [Full Text] [PDF]

				M.J. BISSELL, P.A. KENNY, and D.C. RADISKY Microenvironmental Regulators of Tissue Structure and Function Also Regulate Tumor Induction and Progression: The Role of Extracellular Matrix and Its Degrading Enzymes Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 343 - 356. [Abstract] [PDF]

				C. C. Park, R. L. Henshall-Powell, A. C. Erickson, R. Talhouk, B. Parvin, M. J. Bissell, and M. H. Barcellos-Hoff Ionizing radiation induces heritable disruption of epithelial cell interactions PNAS, September 16, 2003; 100(19): 10728 - 10733. [Abstract] [Full Text] [PDF]

				K. L. Schmeichel and M. J. Bissell Modeling tissue-specific signaling and organ function in three dimensions J. Cell Sci., June 15, 2003; 116(12): 2377 - 2388. [Abstract] [Full Text] [PDF]

				M. Anders, R. Hansen, R.-X. Ding, K. A. Rauen, M. J. Bissell, and W. M. Korn Disruption of 3D tissue integrity facilitates adenovirus infection by deregulating the coxsackievirus and adenovirus receptor PNAS, February 18, 2003; 100(4): 1943 - 1948. [Abstract] [Full Text] [PDF]

				O. W. Petersen, H. L. Nielsen, T. Gudjonsson, R. Villadsen, F. Rank, E. Niebuhr, M. J. Bissell, and L. Ronnov-Jessen Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma Am. J. Pathol., February 1, 2003; 162(2): 391 - 402. [Abstract] [Full Text] [PDF]

				J. Muschler, D. Levy, R. Boudreau, M. Henry, K. Campbell, and M. J. Bissell A Role for Dystroglycan in Epithelial Polarization: Loss of Function in Breast Tumor Cells Cancer Res., December 1, 2002; 62(23): 7102 - 7109. [Abstract] [Full Text] [PDF]

				F. Wang, R. K. Hansen, D. Radisky, T. Yoneda, M. H. Barcellos-Hoff, O. W. Petersen, E. A. Turley, and M. J. Bissell Phenotypic Reversion or Death of Cancer Cells by Altering Signaling Pathways in Three-Dimensional Contexts J Natl Cancer Inst, October 2, 2002; 94(19): 1494 - 1503. [Abstract] [Full Text] [PDF]

				N. D. Zantek, J. Walker-Daniels, J. Stewart, R. K. Hansen, D. Robinson, H. Miao, B. Wang, H.-J. Kung, M. J. Bissell, and M. S. Kinch MCF-10A-NeoST: A New Cell System for Studying Cell-ECM and Cell-Cell Interactions in Breast Cancer Clin. Cancer Res., November 1, 2001; 7(11): 3640 - 3648. [Abstract] [Full Text] [PDF]

				H.-M. Chen, K. L. Schmeichel, I. S. Mian, S. Lelièvre, O. W. Petersen, and M. J. Bissell AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression Mol. Biol. Cell, April 1, 2000; 11(4): 1357 - 1367. [Abstract] [Full Text]

				F. Wang, V. M. Weaver, O. W. Petersen, C. A. Larabell, S. Dedhar, P. Briand, R. Lupu, and M. J. Bissell Reciprocal interactions between beta 1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: A different perspective in epithelial biology PNAS, December 8, 1998; 95(25): 14821 - 14826. [Abstract] [Full Text] [PDF]

				V.M. Weaver, O.W. Petersen, F. Wang, C.A. Larabell, P. Briand, C. Damsky, and M.J. Bissell Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies J. Cell Biol., April 7, 1997; 137(1): 231 - 245. [Abstract] [Full Text] [PDF]