The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein

Sho Yoshioka, Kazuhiro Katayama, Chikako Okawa, Sachiko Takahashi, Satomi Tsukahara, Junko Mitsuhashi, Yoshikazu Sugimoto

研究成果: Article査読

26 被引用数 (Scopus)

抄録

Purpose. We examined the effects of the nine nonsynonymous germ-line mutations/SNPs in the breast cancer resistance protein (BCRP/ABCG2) gene on the expression and function of the protein. Materials and Methods. We generated cDNAs for each of these mutants (G151T, C458T, C496G, A616C, T623C, T742C, T1291C, A1768T, and G1858A BCRP) and compared the effects of their exogenous expression in PA317 cells with a wild-type control. Results. PA/F208S cells (T623C BCRP-transfectants) expressed marginal levels of a BCRP protein species (65kDa), which is slightly smaller than wild-type (70kDa), but this mutant did not appear on the cell surface or confer drug resistance. PA/F431L cells (T1291C BCRP-transfectants) were found to express both 70kDa and 65kDa BCRP protein products. In addition, although PA/F431L cells expressed 70kDa BCRP at comparable levels to PA/WT cells, they showed only marginal resistance to SN-38. PA/T153M cells (C458T BCRP-transfectants) and PA/D620N cells (G1858A BCRP-transfectants) expressed lower amounts of BCRP and showed lower levels of resistance to SN-38 compared with PA/WT cells. Conclusions. We have shown that T623C BCRP encodes a non-functional BCRP and that T1291C BCRP encodes a low-functional BCRP. Hence, these mutations may affect the pharmacokinetics of BCRP substrates in patients harboring these alleles.

本文言語English
ページ(範囲)1108-1117
ページ数10
ジャーナルPharmaceutical research
24
6
DOI
出版ステータスPublished - 2007 6

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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