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In Situ Cross-Linking by Cisplatin of Nuclear Matrix-bound Transcription Factors to Nuclear DNA of Human Breast Cancer Cells¹

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3E OW3 [S. K. S., V. A. S., L. B., J-M. S., L. T. H., J. R. D.]; and Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284 [S. O.]

Cisplatin is an antitumor drug that is used to treat several types of cancers. In this study, we analyzed the proteins that were cross-linked to DNA in situ in MCF-7 human breast cancer cells incubated with cisplatin. We show that cisplatin cross-links nuclear matrix proteins to DNA. In immunoblotting experiments, we found that nuclear matrix-associated transcription factors and cofactors (estrogen receptor, HET/SAF-B, hnRNP K, and histone deacetylase 1) were cross-linked to nuclear DNA. These transcription factors and cofactors have essential roles in the regulation of genes involved in the proliferation of breast cancer cells and in the organization and structure of chromatin. We applied a novel protocol to demonstrate that the nuclear matrix-bound transcription factors/cofactors were cross-linked to DNA fragments attached to the nuclear matrix. These results suggest that the cross-linking of nuclear matrix-associated transcription factors and cofactors to DNA may be one of the mechanisms by which cisplatin inhibits transcription and replication processes.

¹ This research was supported by Medical Research Council of Canada Grants PG-12809 and MT-9186 and United States Army Breast Cancer Postdoctoral Research Grant DAM17-96-1-6269 (to L. T. H.). J. R. D. is a Medical Research Council of Canada Senior Scientist.

² To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E OW3. Phone: (204) 789-3215; Fax: (204) 789-3900; E-mail: davie@cc.umanitoba.ca.

Received 5/ 8/98. Accepted 6/ 1/98.

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