Pharmacogenomics of Human ABC Transporter ABCC11 (MRP8): Potential Risk of Breast Cancer and Chemotherapy Failure

Some genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of certain diseases and patients’ responses to medication. Human ABCC11 functions as an ATP-dependent efflux pump for amphipathic anions. One non-synonymous SNP 538G>A (Gly180Arg) has been found to greatly affect the function and stability of de novo synthesized ABCC11 (Arg180) variant protein. The SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum (ER) and readily undergoes proteasomal degradation. This ER-associated degradation of ABCC11 protein underlies the molecular mechanism of affecting the function of apocrine glands. On the other hand, the wild type (Gly180) of ABCC11 is associated with wettype earwax, axillary osmidrosis, colostrum secretion from the mammary gland, and the potential susceptibility of breast cancer. Furthermore, the wild type of ABCC11 reportedly has ability to efflux cyclic nucleotides and nucleoside-based anticancer drugs. The SNP (538G>A) of the ABCC11 gene is suggested to be a clinical biomarker for prediction of chemotherapeutic efficacy. Major obstacle to the successful chemotherapy of human cancer is development of resistance, and nucleoside-based chemotherapy is often characterized by inter-individual variability. This review provides an overview about the discovery and the genetic polymorphisms in human ABCC11. Furthermore, we focus on the impact of ABCC11 538G>A on the apocrine phenotype, patients’ response to nucleoside-based chemotherapy, and the potential risk of breast cancer

A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene

<p>Abstract</p> <p>Background</p> <p>Two types of cerumen occur in humans: the wet type with brownish, sticky earwax, and the dry type with a lack of or reduced ceruminous secretion. The wet type is common in populations of European and African origin, while the dry type is frequently seen in Eastern Asian populations. An association between axillary odor and the wet-type earwax was first identified approximately 70 years ago. The data were based on a phenotypical analysis of the two phenotypes among the Japanese by a researcher or by self-declaration of the subjects examined, and were not obtained using definite diagnostic methods. Recently, we identified a single-nucleotide polymorphism (SNP; rs17822931) of the <it>ABCC11 </it>gene as the determinant of the earwax types. In the present study, to determine whether the SNP can serve as a diagnostic marker for axillary osmidrosis (AO), we examined genotypes at rs17822931 in 79 Japanese AO individuals. AO was defined here as a clinical condition of individuals with a deep anxiety regarding axillary odor and had undergone the removal of bilateral axillary apocrine glands.</p> <p>Results</p> <p>A comparison of the frequencies of genotypes at rs17822931 in the 79 AO individuals and in 161 Japanese from the general population showed that AO was strongly associated with the wet earwax genotype. A total of 78 (98.7%) of 79 AO patients had either the GG or GA genotype, while these genotypes were observed in 35.4% (57/161) of the subjects from the general population (<it>p </it>< 1.1 × 10^-24, by Fisher's exact test).</p> <p>Conclusion</p> <p>The strong association between the wet-earwax associated <it>ABCC11-</it>genotypes (GG and GA) and AO identified in this study indicates that the genotypes are good markers for the diagnosis of AO. In addition, these results suggest that having the allele G is a prerequisite for the axillary odor expression. In other words, the ABCC11 protein may play a role in the excretory function of the axillary apocrine gland. Together, these results suggest that when an AO individual visiting a hospital is diagnosed with dry-type earwax by <it>ABCC11</it>-genotyping, surgical removal of their axillary glands may not be indicated.</p

ABCC11 (ATP-binding cassette, sub-family C (CFTR/MRP), member 11)

Review on ABCC11, with data on DNA/RNA, on the protein encoded and where the gene is implicated

ゲノムワイド関連解析を用いた日本人女性の皮膚形質に関わる新規15遺伝子領域の同定

博士(医学) 乙第3020号(主論文の要旨、要約、審査結果の要旨、本文)，著者名:Chihiro ENDO・Todd A. JOHNSON・Ryoko MORINO・Kazuyuki NAKAZONO・Shigeo KAMITSUJI・Masanori AKITA・Maiko KAWAJIRI・Tatsuya YAMASAKI・Azusa KAMI・Yuria HOSHI・Asami TADA・Kenichi ISHIKAWA・Maaya HINE・Miki KOBAYASHI・Nami KURUME・Yuichiro TSUNEMI・Naoyuki KAMATANI・Makoto KAWASHIMA, タイトル:Genome-wide association study in Japanese females identifies fifteen novel skin-related trait associations，掲載誌:Scientific reports.(2045-2322)，巻・頁・年:8巻 1号 p.8974(2018)，著作権関連情報:© The Author(s) 2018，DOI:10.1038/s41598-018-27145-2.博士(医学)東京女子医科大

Role of genetic variation in ABC transporters in breast cancer prognosis and therapy response

Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.Czech Medical Council [17-28470A]; Czech Ministry of Education, Youth and SportsMinistry of Education, Youth & Sports - Czech Republic [CZ.02.1.01/0.0/0.0/16_013/0001634]; Grant Agency of Charles University [UNCE/MED/006]; Grant Agency of the Czech RepublicGrant Agency of the Czech Republic [19-03063S

ATP-binding cassette subfamily C (ABCC) transporter 1 (ABCC1) and 4 (ABCC4) independent of their drug efflux ability affects breast cancer biology

Breast cancer treatment has been a challenge to date, due in part to cancer cells acquiring drug resistance. One of the mechanisms by which resistance can occur is the overexpression of drug efflux pumps such as ATP-binding cassette, subfamily C (ABCC) transporter 1(ABCC1) and 4 (ABCC4), which are members of ABC transporters. Recently research has shown that these proteins may be implicated in cancer biology independent of cytotoxic drug efflux, but so far little is known about this in regards to breast cancer. ABCC1 and ABCC4 protein levels in MDA-MB231 and MCF-7, human breast cancer derived cell lines were measured by Western blot. The role of ABCC1 and ABCC4 in cell proliferation and migration were evaluated by colony formation, MTT and scratch assays in the presence of various ABCC inhibitors – MK571, Indomethacin, Reversan, Ceefourin 1 and Ceefourin 2, inhibitors of ABCC4. Similarly the effect on proliferation, migration and invasion was monitored following knock down of ABCC1 and ABCC4 with ABCC1- and ABCC4- specific siRNAs, or overexpression using transfection with pcDNA3.1 plasmids containing the ABCC1 and ABCC4 genes. The potential correlation between ABCC1 and/or ABCC4 and the expression of Gprotein-coupled receptor 55 (GPR55), or extracellular signal-regulated kinase (ERK), or the extracellular efflux of cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), sphingosine-1-phosphate (S1P) and cyteinyl leukotrienes (LTC4, LTD4 and LTE4) were investigated by Western blot and enzyme-linked immunosorbent assays. This thesis demonstrates that the expression levels of ABC transporters varies between breast cancer cell lines. Our results suggest that ABCC1 may be more involved in mediating breast cancer cell proliferation than ABCC4 and in contrary ABCC4 may be involved in mediating breast cancer cell invasion more than ABCC1. There is also an indication that both ABCC1and ABCC4 are implicated in breast cancer migration. In addition, potential correlation between ABCC1 and/or ABCC4 with cAMP or S1P efflux looks promising but further investigation is required. Taken together this thesis shows that ABCC1 and ABCC4 may be implicated in breast cancer development and progression. Further investigations are needed to validate our current results, but ABCC1 and ABCC4 could be potential therapeutic targets for breast cancer

Drug transport and drug-drug interactions at the blood-brain barrier

Membrane transporters are increasingly recognised as being important in determining drug pharmacokinetics at whole body, organ, and cellular levels. At the blood-­‐brain barrier (BBB), membrane transporters determine the passage of drugs into and out of the brain. About 30 % of all patients are classed as non-­‐responders for both epilepsy and schizophrenia. Drug transporters from the adenosine 5'-­‐ triphosphate (ATP)-­‐binding cassette (ABC) transporter family or from the solute carrier (SLC) superfamily may contribute to these drug resistant phenotypes but most have received limited attention. Treatment response to carbamazepine (CBZ) has been associated with genetic polymorphisms in ABCC2, particularly -­‐24C>T, c.1249G>A, and c.3972C>T. However, the results have been conflicting and inconclusive amongst the different studies. A functional and clinical analysis was undertaken to investigate the impact of ABCC2 on CBZ treatment response. In vitro, no ABCC2-­‐mediated CBZ transport could be observed in efflux assays with an ABCC2-­‐transfected human fibrosarcoma cell line (Rht14-­‐10) and a dog kidney cell line (MDCKII). In addition, uptake into inside-­‐out vesicles derived from the Rht14-­‐10 cell line was negative. Clinical analysis of patients from the SANAD (Standard and New Antiepileptic Drugs) trial (assessing the clinical end-­‐points time to first seizure (n = 229) and time to 12-­‐month remission (n = 134)) did not show any significant associations between the three ABCC2 gene polymorphisms, -­‐24C>T, c.1249G>A, c.3972C>T, and clinical outcomes. In an attempt to identify currently unrecognised human drug transporters with potential relevance to epilepsy and schizophrenia, screening of transport of CBZ, lamotrigine (LTG), topiramate (TPM), levetiracetam, valproate, phenytoin, and clozapine (CLP) was undertaken using an immortalised human brain endothelial cell line (hCMEC/D3) as an in vitro model of the BBB. Accumulation of TPM was significantly enhanced by 44-­‐53 % in the presence of the typical ABCC efflux transporter inhibitors MK571 and montelukast. Furthermore, CLP uptake was significantly reduced by 94 % and 83 % in the presence of the typical organic cation transporter inhibitors prazosin and verapamil, respectively. CLP uptake into the hCMEC/D3 cell line followed classical Michaelis-­‐Menten kinetics with Vmax of 3288 (pmol/million cells)/min and Km of 35.93 μM. To identify the exact underlying transporters involved in TPM efflux and CLP uptake, both functional siRNA screening was undertaken and transport was investigated in transfected cell lines. None of the known functional ABCC transporters were shown to transport TPM. In addition, none of the expressed and functionally characterised organic cation transporters from the SLC22A family, as well as transporters from the SLC6A, SLC28A, and SLC29A families, had an effect on CLP accumulation. LTG has recently been identified as a substrate for SLC22A1 (OCT1). Interaction with the human immunodeficiency virus protease inhibitors lopinavir/ritonavir and the antipsychotic CLP was therefore investigated. At clinically relevant concentrations, lopinavir was found to significantly reduce SLC22A1-­‐mediated uptake of LTG by 39 %. In addition, CLP was a potent inhibitor of SLC22A1-­‐mediated LTG uptake yielding an IC50 of 1.8 μM. Similarly low IC50 values were obtained with primary human hepatocytes from two patients (IC50 = 7.9 μM and IC50 = 3.9 μM, respectively) and the hCMEC/D3 cell line (IC50 = 2.0 μM). The clinical consequences of these observations will require further in vivo pharmacokinetic and epidemiological research. In conclusion, the results presented in this thesis demonstrate that membrane transporters can be involved in the passage of AEDs and antipsychotics across the BBB and other membrane barriers. However, currently available in vitro methods proved to be insufficient to identify and characterise the underlying transporters involved and to further evaluate the impact on treatment efficacy. The development of large-­‐scale functional screening methodologies will be crucial for a more systematic and comprehensive understanding of drug transport processes involved in determining access of drugs to the central nervous system. This will help in improving drug efficacy and drug safety, allow prediction of drug-­‐drug interactions, and eventually allowed a more personalised approach to prescribing in diseases such as epilepsy and schizophrenia

ABC Transporters in Human Diseases

Mammalian ATP-binding cassette (ABC) transporters constitute a superfamily of proteins involved in many essential cellular processes. Most of these transporters are transmembrane proteins and allow the active transport of solutes, small molecules, and lipids across biological membranes. On the one hand, some of these transporters are involved in drug resistance (also referred to as MDR or multidrug resistance), a process known to be a major brake in most anticancer treatments, and the medical challenge is thus to specifically inhibit their function. On the other hand, molecular defects in some of these ABC transporters are correlated with several rare human diseases, the most well-documented of which being cystic fibrosis, which is caused by genetic variations in ABCC7/CFTR (cystic fibrosis transmembrane conductance regulator). In the latter case, the goal is to rescue the function of the deficient transporters using various means, such as targeted pharmacotherapies and cell or gene therapy. The aim of this Special Issue, “ABC Transporters in Human Diseases”, is to present, through original articles and reviews, the state-of-the-art of our current knowledge about the role of ABC transporters in human diseases and the proposed therapeutic options based on studies ranging from cell and animal models to patients