title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 70 kDa and 65 kDa BCRP protein products. In addition, although PA/F431L cells expressed 70 kDa 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.
authors: Department of Chemotherapy, Kyoritsu University of Pharmacy, Tokyo, Japan.
authors: Sho
authors: S
authors: Yoshioka
authors: Kazuhiro
authors: K
authors: Katayama
authors: Chikako
authors: C
authors: Okawa
authors: Sachiko
authors: S
authors: Takahashi
authors: Satomi
authors: S
authors: Tsukahara
authors: Junko
authors: J
authors: Mitsuhashi
authors: Yoshikazu
authors: Y
authors: Sugimoto
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers; D018076:DNA, Complementary; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D018076:DNA, Complementary; D009363:Neoplasm Proteins