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Genes Amplified and Overexpressed in Human Multidrug-resistant Cell Lines¹

Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands [A. M. V. d. B., T. V. d. V-K., P. B.]; Massachusetts Institute of Technology, Center for Cancer Research, Cambridge, Massachusetts 02139 [F. B.]; Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [J. L. B., M. B. M.]; Medicine Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205 [R. F. O., T. C. H.]; and Institute of Human Genetics, Free University, 1007 MC Amsterdam, The Netherlands [H. J.]

Multidrug resistance (MDR) is associated with overproduction of M_r 170,000 membrane proteins (P-glycoproteins) caused by either gene amplification, transcriptional activation, or both. In rodents the amplified domain comprises genes that encode P-glycoproteins and at least five unrelated genes, one of which encodes the calcium-binding protein sorcin. The amplification and increased expression of these genes always includes one P-glycoprotein-encoding gene (pgp1 in hamsters, homologous to mdr1 in humans). In human MDR cells only elevated mdr1 expression has been shown thusfar, although another P-glycoprotein encoding gene (mdr3, homologous to hamster pgp3) is closely linked. Here we show that the human homolog of the hamster sorcin gene resides on chromosome 7 like the P-glycoprotein-encoding genes. Furthermore, gene classes designated 4, 5, and 6 are coamplified with mdr1 and mdr3 in the human ovarian carcinoma cell line 2780AD, which strongly suggests that the overall structure of the human MDR domain is the same as in rodents. Class 6 was moderately and mdr1 was highly overexpressed in this cell line. Four other human MDR cell lines also have much higher mdr1 overexpression than expected from the relatively low levels (2- to 30-fold) of gene amplification. This contrasts with the results of previous work with rodent MDR cells, in which the increase in P-glycoprotein mRNA levels usually parallels the increase in gene copy number. Although four of the five human MDR cell lines have coamplified mdr3, its expression was undetectable. Our results confirm the central role of the mdr1 (pgp1) gene in MDR and suggest that different cross-resistance patterns are not due to differential expression of different P-glycoprotein genes.

¹ This work was supported in part by Grant NKI 84-20 of the Queen Wilhelmina Fund to P. B. and by grants from The National Cancer Institute to the Sloan-Kettering Institute (CA-08748) and to J. L. B. (CA-28595). F. B. was supported by the collaborative project on molecular genetics of the University of Amsterdam and The Netherlands Cancer Institute.

² To whom requests for reprints should be addressed, at Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Received 4/18/88. Revised 7/20/88. Accepted 7/26/88.

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