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The 95-Kilodalton Membrane Glycoprotein Overexpressed in Novel Multidrugresistant Breast Cancer Cells Is NCA, the Nonspecific Cross-reacting Antigen of Carcinoembryonic Antigen¹

Greenebaum Cancer Center of the University of Maryland and the Department of Medicine, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201 [D. D. R., Y. G., W. Y., L. A. D.]; The Worcester Foundation, Worcester, Massachusetts 01545 [J. L.]; and the Beckman Institute of the City of Hope, Duarte, California 91010 [J. S.]

Human breast carcinoma MCF-7/AdrVp cells display a novel multidrug resistance phenotype that is characterized by the overexpression of a 95-kDa membrane glycoprotein (p95) and by marked reduction in intracellular anthracycline accumulation, without overexpression of P-glycoprotein or the multidrug resistance protein MRP. p95 is also highly expressed in multidrug-resistant NCI-H1688 cells derived from a human small cell lung carcinoma. Deglycoslyated p95 from NCI-H1688 cells was isolated by two-dimensional gel electrophoresis and then digested with trypsin. The tryptic peptides were analyzed by mass spectrometry and microsequencing. These analyses identified p95 to be identical to NCA-90, the nonspecific cross-reacting antigen related to the carcinoembryonic antigen (CEA). Further confirmation that p95 is indeed NCA-90 was obtained by Northern and Western blot studies using probes or antibodies specific for p95, NCA-90, or CEA family members. Western blot studies also revealed that CEA itself is overexpressed in MCF-7/AdrVp cells compared to parental MCF-7/W cells. The enforced expression of NCA-90 protein in HeLa cells stably transfected with NCA-90 cDNA did not result in increased resistance of the transfected cells to daunorubicin or a decrease in daunorubicin accumulation in the transfected cells compared to cells transfected only with the expression vector. However, a recent report by H. Kawaharata et al. (Int. J. Cancer, 72: 377–382, 1997) of diminished accumulation, retention, and cytotoxicity of doxorubicin in EJNIH3T3 cells in which enforced expression of CEA was accomplished leaves open the possibility that the overexpression of CEA, possibly in combination with that of NCA-90, could account at least in part for the drug resistant phenotype displayed by MCF-7/AdrVp cells.

¹ Supported by Grant R01 CA52178 from the National Cancer Institute, by a United States Department of Veterans Affairs merit review grant (to D. D. R.), by a grant from Pharmacia and Upjohn, Inc., and by a grant from the Charlotte Geyer Foundation.

² To whom requests for reprints should be addressed, at Greenebaum Cancer Center, Room 9-015, BRB, 655 West Baltimore Street, Baltimore, MD 21201. Phone: (410) 328-3685; Fax: (410) 328-6559; E-mail: dross@umcc01.umcc.ab.umd.edu or adoyle@umcc01.umcc.ab.umd.edu.

Received 8/27/97. Accepted 10/29/97.

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