ABCMdb

PMID: 21103975

Meyer zu Schwabedissen HE, Kroemer HK
In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2).
Handb Exp Pharmacol. 2011;(201):325-71., [PubMed]

Sentences

No. Mutations Sentence Comment

75 ABCG2 p.Arg482Gly Indeed, following studies revealed that drug-selected cancer cells used to identify ABCG2-mediated anthracyclin-resistance carry an acquired mutation of amino acid 482 from arginine to glycine or threonine that changed substrate specificity of the transporter (Honjo et al. 2001; Nakanishi et al. 2003a; Robey et al. 2003). Login to comment 76 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Accordingly, treatment of cancer cells has been demonstrated to result in allele (R482G or R482T) specific gene amplification (Bram et al. 2007), explaining the observed cross-resistance pattern for ABCG2 in previous studies. Login to comment 77 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly A similar "false-positive" substrate description has been assumed for the anti-folate drugs methotrexate, ralitrexate (ZD 1694) and GW1843, but the published results on the impact of the acquired ABCG2-mutations (p.ABCG2 R482G, R482T) are not conclusive (Bram et al. 2006; Breedveld et al. 2007; Chen et al. 2003; Mitomo et al. 2003; Shafran et al. 2005; Volk and Schneider 2003). Login to comment 251 ABCG2 p.Gln126* ABCG2 p.Arg575* ABCG2 p.Glu334* To date there are 26 nonsynonymous, five synonymous (c.114T>C, c.369C>T, c.474C>T, c.1098G>A, and c.1425A>G) polymorphisms, three nonsense mutations (Q126X, E334X, and R575X), and one frameshift mutation (c.1515delC) described in healthy individuals or patients (compare Table 3). Login to comment 252 ABCG2 p.Ile206Leu ABCG2 p.Asp620Asn There is profound variability in the minor allele frequencies (AF) of those polymorphisms among populations of different ethnicities, and some of the polymorphisms have been described in single individuals only, such as the c.616A>C, p.I206L (Zamber et al. 2003), the c.2062G>A (p.D620N) (Honjo et al. 2002), and the frameshift mutation c.1515delC (p.AFFVM505-509 ASSLstop) (Itoda et al. 2003). Login to comment 253 ABCG2 p.Asn590Tyr ABCG2 p.Phe431Leu SNPs with low AF including the c.1291T>C (p.F431L, AF 0.006 in Japanese populations), or the c.1768A>T (p.N590Y, AF 0.001-0.003 in Caucasian populations) mutation have been studied for their activity in vitro showing reduced resistance toward known substrates such as SN-38, mitoxantrone, or topotecan, respectively (An et al. 2009; Itoda et al. 2003; Mizuarai et al. 2004; Tamura et al. 2006; Vethanayagam et al. 2005; Yoshioka et al. 2007; Zamber et al. 2003). Login to comment 254 ABCG2 p.Ser441Asn Reduced transport activity was also demonstrated for the c.1322G>A (p.S441N, AF 0.001 in Japanese population) variant. Login to comment 256 ABCG2 p.Phe208Ser Similar results were obtained for the c.623T>C (p.F208S, AF not determined) variant (Nakagawa et al. 2008; Tamura et al. 2006). Login to comment 257 ABCG2 p.Ile206Leu ABCG2 p.Gln166Glu ABCG2 p.Thr153Met ABCG2 p.Ala149Pro ABCG2 p.Pro269Ser ABCG2 p.Arg163Lys ABCG2 p.Phe571Leu No effect on the in vitro transport activity was seen for the missense mutations c.445G>C (p.A149P; AF 0.01), c.458C>T (p.T153M; AF 0.033) c.496C>G (p.Q166E, AF not determined) c.616A>C (I206L AF not determined), c.488G>A (p.R163K AF 0.006), c.805C>T (p.P269S AF 0.006), and c.1711T>A (p.F571L, AF 0.005) (Kondo et al. 2004; Tamura et al. 2006). Login to comment