Suppression of Cell Proliferation by Inhibition of Estrone-3-Sulfate Transporter in Estrogen-Dependent Breast Cancer Cells

Nozawa, Takashi; Suzuki, Masato; Yabuuchi, Hidetake; Irokawa, Masanori; Tsuji, Akira; Tamai, Ikumi

doi:10.1007/s11095-005-7096-0

Cited by 52 publications

(57 citation statements)

References 28 publications

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“…6), hepatocellular carcinomas (11), breast carcinomas (13), and lung cancer (12). In addition, expression of OATP1B1 and OATP1A2 was found in malignant breast cell lines (14,43), and OATP1A2 (and OATP2B1) have also been localized in the blood-tumor barrier of gliomas (44). Recently, Takano and colleagues (2009) have shown in vitro that hepatoma cells made resistant to paclitaxel treatment showed, besides increased P-glycoprotein expression, drastically decreased mRNA expression of SLCO1B3 (45).…”

Section: Discussionmentioning

confidence: 99%

“…9), and in small intestine (10), where its effect on drug absorption and/or elimination needs further investigation. Besides their physiologic expression, many OATPs have been found expressed in certain malignancies like breast, gastrointestinal, and lung cancers (6,(11)(12)(13)(14), where they may well be involved in the tumor uptake of anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice

Steeg

Esch

Wagenaar

et al. 2013

Clinical Cancer Research

113

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Purpose: Organic anion-transporting polypeptide (OATP) drug uptake transporters are thought to play an important role in drug pharmacokinetics and toxicokinetics. We aimed to determine the influence of the individual human OATP1B1, OATP1B3, and OATP1A2 transporters on the in vivo disposition of the anticancer drugs methotrexate and paclitaxel by using liver-specific humanized OATP1A/1B transgenic mice.Experimental Design: Wild-type, Slco1a/1btg , and newly generated Slco1a/1b À/À ;1A2 tg (humanized OATP1B1, OATP1B3, and OATP1A2 transgenic) mice were characterized biochemically and physiologically, and subsequently intravenously dosed with methotrexate or paclitaxel (2 or 10 mg/kg each) for pharmacokinetic analyses.Results: Humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice all showed partial or complete rescue of increased plasma bilirubin levels, but also of the increased plasma levels and decreased liver and small intestinal accumulation of methotrexate observed in Slco1a/1b À/À mice. Furthermore, hepatic expression of OATP1B3 and OATP1A2, but not OATP1B1, resulted in increased liver uptake of paclitaxel (2 mg/kg). At 10 mg/kg, a modest effect of only OATP1A2 on paclitaxel liver uptake was observed. Conclusion: Human OATP1A/1B transporters play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutics methotrexate (organic anion) and paclitaxel (hydrophobic, bulky). Variation in OATP1A/1B activity due to genetic variation and pharmacologic inhibition, or differences in tumor-specific expression levels might therefore affect plasma, tissue, and tumor levels of these drugs in patients, and hence their therapeutic efficacy. Humanized transgenic OATP1A/1B mice will provide excellent tools to further study these aspects in vivo for many (anticancer) drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice

Steeg

Esch

Wagenaar

et al. 2013

Clinical Cancer Research

113

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“…The purpose of this study was to investigate transcript and protein expression of seven OATP isoforms that recognize E3S as a substrate and further evaluate their differential functional role in E3S uptake among immortalized breast epithelial cells, hormone-dependent breast cancer cells, and hormone-independent breast cancer cells. Although previous work reported OATP expression in hormone-dependent breast cancer cells (MCF7, T47D, and ZR75) (Nozawa et al, 2004(Nozawa et al, , 2005Maeda et al, 2010), for the first time, we compared OATP expression and function in immortalized breast epithelial cells (MCF10A), hormone-dependent breast cancer cells (MCF7), hormoneindependent, invasive, and metastatic breast cancer cells (MDA435/LCC6, derived from MDA-MB-435 cells) (Leonessa et al, 1996), hormone-independent and epidermal growth factor receptor overexpressing breast cancer cells (MDA-MB-468) (Armstrong et al, 1994), and triple negative breast cancer cells (MDA-MB-231) (Grü ndker et al, 2010). Confirmed differences in OATP expression between these cell lines may aid in elucidating the basis for the high tumor concentrations of E3S reported in postmenopausal patients with hormone-dependent breast cancers.…”

Section: Introductionmentioning

confidence: 91%

“…This suggests that OATPs are involved in E3S uptake by breast cancer cells. Furthermore, Nozawa et al (2004Nozawa et al ( , 2005 showed that inhibition of an E3S transporter results in the suppression of hormone-dependent breast cancer cell proliferation (MCF7 and T47D cells). These data suggest a potential role of OATPs in hormone-dependent breast cancers proliferation by facilitating E3S cellular uptake.…”

Section: Introductionmentioning

confidence: 99%

Differential Role of Organic Anion-Transporting Polypeptides in Estrone-3-Sulphate Uptake by Breast Epithelial Cells and Breast Cancer Cells

Banerjee

Allen²,

Bendayan³

2012

J Pharmacol Exp Ther

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The purpose of this study was to investigate the differential expression and function of organic anion-transporting polypeptides (OATPs) in breast epithelial and breast cancer cells. Estrone-3-sulfate (E3S), a substrate for 7 of 11 OATPs, is a predominant source of tumor estrogen in postmenopausal, hormonedependent patients with breast cancer. Overexpression of certain OATPs (e.g., OATP1A2) reported in breast tumor tissues compared with surrounding normal tissues could contribute toward two to three times higher tumoral E3S concentration. Little is known about expression and function of other OATP family members among breast epithelial and breast cancer cells. We therefore compared gene and protein expression of seven OATPs (OATP1A2,OATP1B1,OATP1B3,OATP1C1,OATP2B1,OATP3A1, and OATP4A1) in immortalized breast epithelial cells (MCF10A), hormone-dependent breast cancer cells (MCF7), and hormoneindependent breast cancer cells (MDA/LCC6-435, MDA-MB-231, and MDA-MB-468) by quantitative polymerase chain reaction and immunoblotting, respectively. Expression of solute carrier superfamily encoding for OATPs (SLCO) 1A2, 1B1, 1B3, 2B1, and 3A1 is exclusive, similar, or significantly higher in cancer cells compared with MCF10A cells. Protein expression of OATPs is found to be either exclusive or higher in cancer cells compared with MCF10A cells. Specificity of OATP-mediated E3S uptake is observed only in cancer cells, with the highest total uptake in MCF7 cells. Transport kinetics of E3S uptake demonstrates transport efficiency that is 10 times greater in the MCF7 cells than in the hormone-independent cells. These data suggest that OATPs could be a novel therapeutic target for hormone-dependent breast cancers, particularly in postmenopausal patients, where the major source of tumor estrogen is E3S.

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“…The physiological roles of these transporters are not yet fully understood, but there is compelling evidence that certain members of the OATP family promote cell proliferation and survival of human malignant tissues. We have previously shown that transport of estrone 3-sulfate via OATPs sustains the growth of hormone-dependent human breast cancer cells [7,8], because estrone-3-sulfate can be hydrolyzed by steroid sulfatase (STS) to estrone and eventually estradiol. We recently showed that OATP1B3 contributes to estrone 3-sulfate uptake in estrogen receptor-positive human breast cancer MCF-7 cells [9].…”

Section: Introductionmentioning

confidence: 99%

Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: Possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions

Arakawa

Nakanishi

Yanagihara

et al. 2012

Biochemical Pharmacology

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The biological mechanisms underlying castration resistance of prostate cancer are not fully understood. In the present study, we examined the role of organic anion transporting polypeptides (OATPs) as importers of dehydroepiandrosterone sulfate (DHEAS) into cells to support growth under androgen-depleted conditions. Cell growth and mRNA expression of OATP genes were studied in human prostate cancer LNCaP and 22Rv1 cells under androgen-depleted conditions. The stimulatory effect of DHEAS on cell growth was investigated in LNCaP cells in which OATP1A2 had been silenced. Growth of both cell lines was stimulated by DHEAS and the effect was attenuated by STX64, an inhibitor of steroid sulfatase which can covert DHEAS to DHEA. OATP1A2 mRNA expression was increased most prominently among various genes tested in LNCaP cells grown in androgen-depleted medium. Similar results were obtained with 22Rv1 cells. Furthermore, the characteristics of

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Suppression of Cell Proliferation by Inhibition of Estrone-3-Sulfate Transporter in Estrogen-Dependent Breast Cancer Cells

Cited by 52 publications

References 28 publications

Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice

Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice

Differential Role of Organic Anion-Transporting Polypeptides in Estrone-3-Sulphate Uptake by Breast Epithelial Cells and Breast Cancer Cells

Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: Possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions

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