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Laing NM , Belinsky MG , Kruh GD , Bell DW , Boyd JT , Barone L , Testa JR , Tew KD
Amplification of the ATP-Binding cassette 2 transporter gene is functionally linked with enhanced efflux of estramustine in ovarian carcinoma cells
Cancer Research. 1998 Apr 1;58(7) :1332-1337
AbstractAn estramustine-resistant human ovarian carcinoma cell line, SKEM, was generated to explore resistance mechanisms associated with this agent. Cytogenetic analysis revealed that SKEM cells have a homogeneously staining region (hsr) at chromosome 9q34. Mitrodissection of the hsr, followed by fluorescence in situ hybridization to SKEM and normal metaphase spreads, confirmed that the amplified region was derived from sequences from 9q34. In situ hybridization with a probe specific for ABC2, a gene located at 9q34 that encodes an ATP binding cassette 2 (ABC2) transporter, indicated that this gene is amplified similar to 6-fold in the estramustine-resistant cells. Southern analysis confirmed that ABC2 was amplified in SKEM, and Northern analysis indicated that the ABC2 transcript was overexpressed similar to 5-fold. The ABC1 gene located at 9q22-31 was not amplified in the resistant cells, and mRNA levels of several other ABC transporter genes were unaltered. Consistent with the concept that in creased ABC2 expression contributes to the resistant phenotype, we observed that the rate of emus of dansylated estramustine was increased in SKEM compared with control cells, in addition, antisense treatment directed toward ABC2 mRNA sensitized the resistant cells to estramustine. Together, these results suggest that amplification and overexpression of ABC2 contributes to estramustine resistance and provides the first indication of a potential cellular function for this product.
NotesTimes Cited: 11 English Article ZE314 CANCER RES