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JNCI Journal of the National Cancer Institute 2001 93(10):776-782; doi:10.1093/jnci/93.10.776
© 2001 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 93, No. 10, 776-782, May 16, 2001
© 2001 Oxford University Press

REPORT

Progressive Resistance to Apoptosis in a Cell Lineage Model of Human Proliferative Breast Disease

Susan L. Starcevic, Cornelis Elferink, Raymond F. Novak

Affiliation of authors: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI.

Correspondence to: Raymond F. Novak, Ph.D., Institute of Environmental Health Sciences (formerly the Institute of Chemical Toxicology), 2727 Second Ave., Wayne State University, Detroit, MI 48201 (e-mail: raymond.novak{at}wayne.edu).

Background: Proliferative breast disease (PBD) may increase a woman's risk of developing breast cancer, perhaps by decreasing cellular sensitivity to apoptosis. To determine whether resistance to apoptosis develops during PBD, we investigated apoptosis initiated through the Fas pathway in a series of cell lines that recapitulates the morphologic changes of PBD in nude/beige mice. Methods: The series of cell lines used was MCF-10A cells (parental preneoplastic human breast epithelial cells), MCF-10AT cells (transformed with T24 Ha-ras), and MCF-10ATG3B cells (derivative cells that progress to carcinoma). Fas-mediated apoptosis, induced when a Fas monoclonal antibody bound to and activated the Fas receptor on these cells, was assessed morphologically and by flow cytometry. Levels of proteins involved in Fas-mediated apoptosis and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP), an end product of caspase activation, were determined by immunoblotting. Bcl-2 and Bax heterodimerization was examined by coimmunoprecipitation. All statistical tests were two-sided. Results: Sensitivity to Fas-mediated apoptosis decreased with the tumorigenic potential of cells: MCF-10A cells were extremely susceptible, MCF-10AT cells were less susceptible, and MCF-10ATG3B cells were resistant. The percentage of apoptotic cells declined, from 24% to 8% to 6%, respectively. All lines produced Fas ligand (FasL) and had comparable levels of Fas receptor, FasL, Fas-associated death-domain protein, and caspases 3 and 6. Levels of caspase 8 were similar in MCF-10A and MCF-10AT cells but about 30% lower in MCF-10ATG3B cells (P>.01 but <.05). Levels of caspase 10 were about 20% lower in MCF-10AT cells (P>.005 but <.01) and about 59% lower in MCF-10ATG3B cells than in MCF-10A cells (P>.01 but <.05). PARP cleavage was detected in MCF-10A and MCF-10AT cells but not in MCF-10ATG3B cells. Levels of Bax, Bid, and Bak proteins were similar in all lines, but levels of Bcl-2 were lower in MCF-10AT and MCF-10ATG3B cells than in MCF-A cells, and Bcl-2–Bax heterodimerization progressively declined in the series. Conclusion: Resistance to Fas-mediated apoptosis appears to develop progressively in the MCF-10AT cell series.


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