A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer

Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan M.; Danesi, Romano; Venzon, David; Baum, Caitlin E.; Gulley, James L.; Price, Douglas K.; Dahut, William L.; Figg, William D.

doi:10.1111/j.1464-410x.2008.07629.x

Cited by 55 publications

(55 citation statements)

References 16 publications

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“…Consistent with findings reported by Hamada and colleagues (2), Sharifi and colleagues (3), and Yang and colleagues (4) in studies of men with advanced prostate cancer receiving androgen deprivation therapy (ADT), we show that a high-testosterone import allele of SLCO1B3 SNP rs4149117 is also associated with an increased risk of prostate cancer-specific mortality (PCSM) in a population-based study of incident prostate cancer cases. Although the associated HRs in each study are small, the consistency of the observation is striking given the differences in the prostate cancer populations under evaluation.…”

supporting

confidence: 78%

SLCO Transport Genes in Prostate Cancer—Response

Mostaghel¹,

Wright²,

Montgomery³

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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We thank Figg and colleagues for their interest in our manuscript (1) and their comments about the potential role of organic anion-transporting polypeptide (OATP) transport proteins in prostate cancer outcomes. Consistent with findings reported by Hamada and colleagues (2), Sharifi and colleagues (3), and Yang and colleagues (4) in studies of men with advanced prostate cancer receiving androgen deprivation therapy (ADT), we show that a high-testosterone import allele of SLCO1B3 SNP rs4149117 is also associated with an increased risk of prostate cancer-specific mortality (PCSM) in a population-based study of incident prostate cancer cases. Although the associated HRs in each study are small, the consistency of the observation is striking given the differences in the prostate cancer populations under evaluation.As discussed by Figg and colleagues in their letter, our work and the work by Yang and colleagues (4) reported different findings for the SLCO2B1 SNP rs12422149 [which encodes for a dehydroepiandrosterone (DHEA) sulfate (DHEAS) transporter]. Whereas Yang and colleagues observed a more rapid time to progression on ADT in men bearing a high-DHEAS import allele of SLCO2B1 SNP rs12422149, we observed an increased risk of PCSM in men bearing the lowimport allele. Certainly, differences could be due to chance alone, and a major challenge of this type of work has been the inconsistent confirmatory findings of SNP studies. As previously discussed, our study evaluated a different cohort of patients from those analyzed by Yang, Hamada, and Sharifi, and the role of OATP proteins over the entire life of the patients in our population may vary from that observed in patients with advanced disease on ADT. We agree with the statement of Figg and colleagues that DHEAS uptake by OATP2B1 is likely most important in men with reduced circulating androgens. Furthermore, while the men who died of prostate cancer in our study likely were on ADT at time of death, we also agree that DHEAS uptake is unlikely to be the mechanism by which this SLCO2B1 SNP is associated with PCSM under these conditions.Steroids represent a small subset of the wide range of endogenous and exogenous substrates transported by OATP proteins, including agents such as statins, cardiac glycosides, glitazones, metformin (and even taxanes; refs. 5, 6), all with known or postulated impacts on prostate carcinogenesis and/or progression (7-13). Given the lengthy natural history of prostate cancer in men with localized disease receiving definitive therapy (in our study, 59% of cases underwent prostatectomy and 27% radiation), genetic variation in uptake and exposure to agents, such as these, represent alternative hypotheses for the impact of OATP transporters on prostate cancer outcomes. We look forward to further studies delineating the mechanisms and contribution of SLCO genes to prostate cancer biology and outcomes.

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supporting

confidence: 78%

SLCO Transport Genes in Prostate Cancer—Response

Mostaghel¹,

Wright²,

Montgomery³

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Leuprolide and goserelin Reduced transport of testosterone with the 334G/699A haplotype [24] Increased progression-free survival in patients with 334G/699A haplotype [97] consequences of the 2677G[T/A polymorphism may be explained by expression alterations alone and not necessarily by altered substrate binding or transport efficiency of the protein. Some postulate that polymorphisms encoding rarer codons for the same amino acid (a synonymous or silent mutation) result in decreased translation efficiency of the mRNA, resulting in lower protein levels.…”

Section: Oatp1b3mentioning

confidence: 98%

Pharmacogenetics of Membrane Transporters: An Update on Current Approaches

et al. 2009

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This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.

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“…Gain-of-function in the androgen pathway involves sensitization of cells to low serum levels of androgens (39), and the development of androgen-independent disease is associated with up-regulation of genes that are involved in the synthesis of androgens (40). Because the WT allele of OATP1B3 is more active than the variant allele in mediating intracellular transport of testosterone, the enhanced uptake of androgens in patients may shorten the time to androgen independence (41). We are actively investigating this possibility by examining the association between SLCO1B3 genotype and the development of androgen-independent tumors.…”

Section: Discussionmentioning

confidence: 99%

Effect of SLCO1B3 Haplotype on Testosterone Transport and Clinical Outcome in Caucasian Patients with Androgen-Independent Prostatic Cancer

Hamada

Sissung²,

Price

et al. 2008

Clinical Cancer Research

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Purpose: The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of SLCO1B3 haplotype on clinical outcome of Caucasian patients with androgen-independent prostatic cancer. Experimental Design: SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, whereas testosterone transport was analyzed in Cos-7 cells transfected with WT, 334G, and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy, and the relationship between SLCO1B3 haplotypes and survival was examined in patients. Results: Cells transfected with wild-type (334T/699G) SLCO1B3, or with a vector containing either the 334G or 699A variants, actively transported testosterone, whereas its uptake was impaired in cells transfected with a gene carrying both 334G and 699A single nucleotide polymorphisms. Prostatic cancer overexpresses OATP1B3 compared with normal or benign hyperplastic tissue; patients with SLCO1B3 334GG/699AA haplotype showed longer median survival (8.5 versus 6.4 years; P = 0.020) and improved survival probability at 10 years (42% versus 23%; P < 0.023) than patients carryingTT/AA and TG/GA haplotypes. Conclusions: The common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostatic cancer.

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A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer

Cited by 55 publications

References 16 publications

SLCO Transport Genes in Prostate Cancer—Response

SLCO Transport Genes in Prostate Cancer—Response

Pharmacogenetics of Membrane Transporters: An Update on Current Approaches

Effect of SLCO1B3 Haplotype on Testosterone Transport and Clinical Outcome in Caucasian Patients with Androgen-Independent Prostatic Cancer

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