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• W2138215087 abstract "PharmacogenomicsVol. 13, No. 6 EditorialFree AccessRecent advances in pharmacogenomics of ABC transporters involved in breast cancer therapyToshihisa IshikawaToshihisa IshikawaOmics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. Search for more papers by this authorEmail the corresponding author at toshi-i@gsc.riken.jpPublished Online:19 Apr 2012https://doi.org/10.2217/pgs.12.41AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: 5-fluorouraciladverse reactiondoxorubicingefitinibmitoxantronmultidrug resistancepersonalized medicinetamoxifentegafurtopotecanPharmacogenomics in breast cancer research & therapyBreast cancer is the most common cancer among women in the industrialized world, where it accounts for 22% of all cancers in women. Accumulating evidence suggests that genetic predispositions are associated with the cause of breast cancer [1]. Germline variants, as well as somatic mutations, are considered as biomarkers to understand breast cancer susceptibility and/or a patients’ response to chemotherapy. The knowledge of pharmacogenomics is fundamental, and its clinical application to diagnosis and treatments of cancer is becoming increasingly important.Understanding the molecular mechanisms and clinical relevance of interindividual variability in drug response remains a great challenge. Pharmacogenomics, the study of genetic variation in the genes that influence drug effect, can provide insight into interindividual variability and a more accurate prediction of drug response than may be obtained by relying solely on a patient’s clinical information. Membrane transporters have been increasingly recognized as contributing to variability in drug exposure and response. Indeed, they are important factors when we evaluate the benefit and/or risk of drugs during development and regulatory review [2]. The goal of drug transporter pharmacogenomics is to understand the impact of genetic variation on the function of transporters that interact with medications. For many drugs in clinical use, transporters are important determinants of absorption, tissue accumulation, and elimination from the body, and thereby transporters significantly influence drug efficacy and toxicity. Adverse drug reactions can result from toxicity associated with high drug concentrations, whereas lack of efficacy can result from reduced therapeutic drug exposure and/or mutations of drug targets. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets can be used to predict toxicity and response to pharmacologic agents used in breast cancer treatments.Genetic polymorphisms in human ATP-binding cassette transporter genesDuring the past two decades, our knowledge has been accumulating in terms of clinical significance of drug transporters, such as ATP-binding cassette (ABC) transporters and solute carrier transporters. These transporters are expressed at numerous epithelial barriers, such as intestinal epithelial cells, hepatocytes, renal tubular cells, the blood–brain barrier and importantly in cancer cells [2]. Currently available evidence strongly suggests that drug transporters are a critical determinant, not only for the pharmacokinetics profile of a drug in the host body, but also for the distribution of anticancer drugs in the cancer tissue.The human ABC transporter family comprises a total of 48 members, some of which are able to transport a variety of compounds, including metabolites and drugs, through membranes at the cost of ATP hydrolysis. Besides drug transport, certain ABC transporters play a role in the transport of lipids, bile salts, toxic compounds and peptides for antigen presentation or other purposes, such as ion-channel regulation. At least 14 of the human ABC transporter genes are reportedly associated with heritable human diseases that are rare and heavily transmitted in families. Mutations in ABC transporter genes have been reported to be associated with inherited diseases, such as cystic fibrosis, Dubin–Johnson syndrome, progressive familial intrahepatic cholestasis, Stargardt disease, Tangier disease T1, Zellweger syndrome, sitosterolemia, retinitis pigmentosa, age-related macular degeneration, pseudoxanthoma elasticum, X-linked adrenoleukodystrophy and gout [3].ABC transporters in multidrug resistance in breast cancerCancer is one of the gene-associated diseases where multiple factors are involved in its cause and development. Hitherto, enormous efforts were made to develop new agents for cancer chemotherapies; however, often these therapies are effective only in a relatively small proportion of cancer patients. Acquired and intrinsic drug resistance in cancer is the major obstacle to long-term, sustained patient response to chemotherapy. It is true that the effectiveness of anticancer drugs can vary significantly among individual patients. It is also well documented that the susceptibility of cancer cells to particular anticancer drugs cannot be predicted by a single factor, but is determined by multiple factors that influence overall sensitivity.Active export of anticancer drugs from cancer cells is one of the major mechanisms of drug resistance. Based on in vitro studies, certain ABC transporters have been implicated to underlie the drug-resistance mechanism in cancer cells by actively extruding the clinically administered chemotherapeutic drugs. To date, the best known major ABC transporters are ABCB1 (P-glycoprotein or MDR1), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT) and ABCG2 (BCRP) [4]. These have been characterized in detail, with respect to their structure and function. Historically, P-glycoprotein was first identified because of its overexpression in cultured cancer cells associated with an acquired cross-resistance to multiple anticancer drugs [5]. Since the discovery of P-glycoprotein and the MDR1 gene, a large number of in vitro and in vivo studies have been carried out to uncover a latent link between the overexpression of ABC transporters and poor outcome in chemotherapy of different cancer types. Numerous attempts were also made to develop inhibitors specific for such ABC transporters; to date no single chemical entity of those inhibitors has been launched on the market.In order to gain more insight into the issue, Rottenberg et al. recently developed a genetically engineered mouse model (Brca1-/-; p53-/-) for human BRCA1-related breast cancer [6]. The authors clearly demonstrated that acquired doxorubicin resistance in the animal model was associated with increased expression of the Abcb1 gene. It is of importance to note that even moderate increases of Abcb1a/1b (as low as fivefold) are sufficient to cause doxorubicin resistance [7]. On the other hand, more than 50 SNPs and several insertion/deletion polymorphisms in the human ABCB1 gene have been reported. With respect to the pharmacogenomics of ABCB1 involved in cancer chemotherapy, further clinical studies are needed to elucidate the impact of those SNPs on the interindividual variability in drug response.Pharmacogenomics of ABC transporter ABCG2 (BCRP)Human ABCG2 is another member of the ABC transporter family. This ABC transporter was discovered in a doxorubicin-resistant breast cancer cell line in vitro[8]. The same gene was independently cloned from a drug-resistant cancer cell line selected with mitoxantrone that is used in the treatment of metastatic breast cancer, acute myeloid leukemia and non-Hodgkin’s leukemia. Sequencing of the ABCG2 gene from human samples has revealed over 80 different, naturally occurring sequence variations [9]. The most extensively studied among those SNPs with potential clinical relevance is 421C>A resulting in a glutamic acid to lysine substitution (Q141K) in the ABCG2 protein. The expression level of the Q141K variant reduced compared with the wild-type, which is due to its ubiquitin-mediated proteasomal degradation [10]. Patients carrying this SNP were found to have elevated plasma levels of gefitinib, diflomotecan and increased bioavailability of oral topotecan. Furthermore, the Q141K SNP was reportedly associated with a higher incidence of diarrhea in non-small-cell lung cancer patients treated with gefitinib [11].Involvement of CYP2D6 & ABCC2 (MRP2) in tamoxifen-based therapyTamoxifen has been widely used for the treatment and prevention of recurrence in patients with estrogen receptor-positive or progesterone receptor-positive breast cancers. Tamoxifen is a prodrug that requires metabolic activation to elicit its activity, where 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are active metabolites. CYP2D6 is a key enzyme in the metabolic activation of tamoxifen [12]. In a certain subpopulation of patients, loss or decrease of CYP2D6 function by genetic polymorphisms was found to be associated with poorer clinical outcome of tamoxifen treatment. Kiyotani et al. have recently reported that one SNP located in intron 29 of the ABCC2 gene was associated with recurrence-free survival in patients receiving tamoxifen monotherapy [13,14]. It is important to note that no significant differences were observed in steady-state plasma concentrations of endoxifen between genotypes of the ABCC2 gene. One plausible explanation is that ABCC2 might regulate local exposure of endoxifen in breast cancer tissue. Nevertheless, genetic polymorphisms in CYP2D6 and ABCC2 are considered as useful biomarkers to predict the clinical outcome of tamoxifen-based therapy for breast cancer patients.Involvement of CYP2A6 & ABCC11 (MRP8) in 5-fluorouracil-based chemotherapyTS-1 is an oral fluorouracil anticancer drug that contains tegafur, the pro-drug of 5-fluorouracil (5-FU). To exert its anti-tumor effect, tegafur must be converted to 5-FU, an inhibitor of dihydropyridine dehydrogenase. Hepatic CYP2A6 plays a key role in the metabolic conversion of tegafur to 5-FU [15]. Patients with the CYP2A6*4C allele (e.g., whole deletion of the CYP2A6 gene) were shown to have significantly low plasma concentrations of 5-FU [16]. In this context, response to tegafur-based therapy was significantly lower in those patients.More recently, it has been reported that the wild-type of ABCC11 has the ability to efflux cyclic nucleotides and nucleoside-based anticancer drugs. ABCC11 wild-type is involved in 5-FU resistance by the efflux transport of the active metabolite 5-fluoro-2´-deoxyuridine 5´-monophosphate (FdUMP) [17]. ABCC11 mRNA is highly expressed in breast tumors, in particular, in invasive ductal adenocarcinomas. On the other hand, one nonsynonymous SNP, 538G>A (Gly180Arg), in the ABCC11 gene greatly affects the function and stability of the de novo synthesized variant protein. The SNP (Arg180) variant is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes proteasomal degradation. This endoplasmic reticulum-associated degradation of the ABCC11 protein (Arg180) underlies the molecular mechanism for the reduced transport activity of ABCC11 [18]. Thus, the SNP (538G>A) of the ABCC11 gene is suggested to be a clinical biomarker for prediction of chemotherapeutic efficacy. It has previously been reported that this SNP could be a biomarker for prediction of breast cancer risk or mastopathy in Japanese women [19,20], whereas no significant association with breast cancer risk was observed in Europeans [21]. Further clinical validation will be needed to clarify the potential contribution of ABCC11 to breast cancer prognosis, including drug resistance and chemosensitivity.ConclusionThere is a critical need for targeted therapies in the treatment of human tumors. Multidrug resistance ABC transporters were originally discovered because their overexpression is related with a broad spectrum of resistance of cancer cells to structurally diverse chemotherapeutic agents. In order to circumvent multidrug resistance of cancer, a large number of studies and trials have been conducted in order to develop specific inhibitors of multidrug resistance ABC transporters [4]. Recent studies, on the other hand, have revealed that genetic polymorphisms and mutations in ABC transporter genes are biomarkers for diagnosis of inherited diseases and are able to predict the risk of drug-induced adverse reactions or response to chemotherapy. By understanding the genetic basis of the activity of ABC transporters, it will be possible to enhance a predictive approach to individualization of drug therapy for breast cancer and other tumors.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Lymberis SC, Parbar PK, Katsoulakis E, Formenti SC. Pharmacogenomics and breast cancer. Pharmacogenomics5,31–55 (2004).Link, CAS, Google Scholar2 Giacomini KM, Huang SM, Tweedie DJ et al. Membrane transporters in drug development: report from the FDA critical path initiative-sponsored workshop. Nature Rev. Drug Discovery9,215–236 (2010).Crossref, Medline, CAS, Google Scholar3 Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem.71,537–592 (2002).Crossref, Medline, CAS, Google Scholar4 Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer, role of ATP-dependent transporters. Nat. Rev. Cancer2,48–58 (2002).Crossref, Medline, CAS, Google Scholar5 Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science221,1285–1288 (1983).Crossref, Medline, CAS, Google Scholar6 Rottenberg S, Nygren AO, Pajic M et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA104,12117–12122 (2007).Crossref, Medline, CAS, Google Scholar7 Pajic M, Iyer JK, Kersbergen A et al. Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer. Cancer Res.69,6396–6404 (2009).Crossref, Medline, CAS, Google Scholar8 Doyle LA, Yang W, Abruzzo LV et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA95,15665–15670 (1998).Crossref, Medline, CAS, Google Scholar9 Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design. Naturwissenschaften92,451–463 (2005).Crossref, Medline, CAS, Google Scholar10 Nakagawa H, Toyoda Y, Wakabayashi-Nakao K, Tamaki H, Osumi M, Ishikawa T. Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts. J. Parm. Sci.100,3602–3619 (2011).Crossref, Medline, CAS, Google Scholar11 Cusatis G, Gregorc V, Li J, Spreafico A et al. Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J. Natl Cancer Inst.98,1739–1742 (2006).Crossref, Medline, CAS, Google Scholar12 Deahal SS, Kupfer D. CYP2D6 catalyzes tomoxifen 4-hydroxylation in human liver. Cancer Res.57,3402–3406 (1997).Medline, Google Scholar13 Kiyotani K, Mushiroda T, Imamura CK et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J. Clin. Oncol.28,1287–1293 (2010).Crossref, Medline, CAS, Google Scholar14 Kiyotani K, Mushiroda T, Tsunoda T et al. A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese. Hum. Mol. Genet.21(7),1665–1672 (2012).Crossref, Medline, CAS, Google Scholar15 Ikeda K, Yoshisue K, Matsushima E et al. Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. Clin. Cancer Res.6,4409–4415 (2000).Medline, CAS, Google Scholar16 Wang H, Bian T, Liu D et al. Association analysis of CYP2A6 genotypes and haplotypes with 5-fluorouracil formation from tegafur in human liver microsomes. Pharmacogenomics12,481–492 (2011).Link, CAS, Google Scholar17 Oguri T, Bessho Y, Achiwa H et al.MRP8/ABCC11 directly confers resistance to 5-fluorouracil. Mol. Cancer Ther.6,122–127 (2007).Crossref, Medline, CAS, Google Scholar18 Toyoda Y, Sakurai A, Mitani Y et al. Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type? FASEB J.23,2001–2013 (2009).Crossref, Medline, CAS, Google Scholar19 Petrakis NL. Cerumen genetics and human breast cancer. Science173,347–349 (1971).Crossref, Medline, CAS, Google Scholar20 Toyoda Y, Ishikawa T. Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential risk of breast cancer and chemotherapy failure. Anticancer Agents Medicinal Chem.10,617–624 (2010).Crossref, Medline, CAS, Google Scholar21 Lang T, Justenhoven C, Winter S et al. The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans. Breast Cancer Res. Treat.129,993–999 (2011).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByImpact of variants in ATP-binding cassette transporters on breast cancer treatmentQingyang Xiao, Yitian Zhou & Volker M Lauschke23 November 2020 | Pharmacogenomics, Vol. 21, No. 18Synthesis of Ferrocene Based Naphthoquinones and its Application as Novel Non‐enzymatic Hydrogen Peroxide4 February 2020 | Electroanalysis, Vol. 32, No. 6ABCB1 variants (C1236T, rs1128503 and G2677T/A, rs2032582) do not show an association with recurrence and survival in patients with breast cancer undergoing anthracycline-based chemotherapyMeta Gene, Vol. 21Different dynamics of thyroglobulin after thyroid extirpation, depending on the thyroid statusLaboratornaya sluzhba, Vol. 6, No. 3Glyco-redox, a link between oxidative stress and changes of glycans: Lessons from research on glutathione, reactive oxygen and nitrogen species to glycobiologyArchives of Biochemistry and Biophysics, Vol. 595Breast cancer pharmacogenomics: where we are goingWilliam G Newman & Dave Flockhart19 April 2012 | Pharmacogenomics, Vol. 13, No. 6 Vol. 13, No. 6 Follow us on social media for the latest updates Metrics History Published online 19 April 2012 Published in print April 2012 Information© Future Medicine LtdKeywords5-fluorouraciladverse reactiondoxorubicingefitinibmitoxantronmultidrug resistancepersonalized medicinetamoxifentegafurtopotecanFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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