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Human Breast Cancer Cells Contain an Error-prone DNA Replication Apparatus¹

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine [J. W. S., L. H. M., P. E. B., B. J. L., R. J. H.]; Greenebaum Cancer Center [R. J. H.]; Program in Oncology, Greenebaum Cancer Center [L. H. M.]; Programs in Molecular and Cellular Biology [L. H. M., R. J. H.] and Toxicology [L. H. M., R. J. H.], University of Maryland; and Greater Baltimore Medical Center, Comprehensive Breast Care Center [L. S.], Baltimore, Maryland 21201

The mechanisms responsible for creating genetic errors and genomic instability in cancer cells have not been fully defined. Recently, it has been shown that human cells contain a highly organized complex of proteins, termed the DNA synthesome, that is fully competent to carry out all phases of SV40 in vitro DNA replication (J. M. Coll et al., Oncol. Res., 8: 435–447, 1996; L. H. Malkas et al., Biochemistry, 29: 6362–6374, 1990; Y. Wu et al., J. Cell. Biochem., 54: 32–46, 1994; N. Applegren et al., J. Cell. Biochem., 54: 32–46, 1994). DNA replication fidelity analyses of the DNA synthesome derived from malignant and nonmalignant human breast cells demonstrate that the malignant cell synthesome is mutagenic. The decrease in tumor cell replication fidelity was not due to an increased proliferative capacity of the tumor cells or an increase in the synthetic activity of their DNA synthesome. The ratios of insertions, deletions, and mismatches created by the synthesome from malignant and nonmalignant breast cells were essentially identical, despite the greater overall number of mutations made by the breast cancer cell synthesome. These data define, for the first time, a mechanism unique to cancer cells that contributes to the observed increase in genetic mutation in cancer cells.

¹ This work was supported by the United States Army Medical Research and Material Command [to J.W.S. (Grant DAMD17-94-J-4151) and P.E.B.]; National Cancer Institute Grants RO1-CA57350, RO1-CA73060, and RSS-CA65754 (to L.H.M.); the University of Maryland Greenebaum Cancer Center (to R.J.H.); and NIH/National Cancer Institute Grant RO1-CA74904 (to R.J.H.).

² To whom requests for reprints should be addressed, at The Department of Pharmacology and Experimental Therapeutics, University of Maryland, 665 West Baltimore Street, BRB Room 4-002, Baltimore, MD 21201. Phone: (410) 328-7499; Fax: (410) 706-0032; E-mail: rhickey@umaryland.edu.

Received 4/14/98. Accepted 6/24/98.

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