Skip to main content

Advertisement

SpringerLink
Log in

Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Two-thirds of newly diagnosed hormone-dependent (HR+) breast cancers are detected in post-menopausal patients where estrone-3-sulphate (E3S) is the predominant source for tumour estradiol. Understanding intra-tumoral fate of E3S would facilitate in the identification of novel molecular targets for HR + post-menopausal breast cancer patients. Hence this study investigates the clinical expression of (i) organic anion-transporting polypeptides (OATPs), (ii) multidrug resistance protein (MRP-1), breast cancer resistance proteins (BCRP), and (iii) sulphatase (STS), 17β-hydroxysteroid dehydrogenase (17β-HSD-1), involved in E3S uptake, efflux and metabolism, respectively. Fluorescent and brightfield images of stained tumour sections (n = 40) were acquired at 4× and 20× magnification, respectively. Marker densities were measured as the total area of positive signal divided by the surface area of the tumour section analysed and was reported as  % area (ImageJ software). Tumour, stroma and non-tumour tissue areas were also quantified (Inform software), and the ratio of optical intensity per histologic area was reported as  % area/tumour,  % area/stroma and  % area/non-tumour. Functional role of OATPs and STS was further investigated in HR+ (MCF-7, T47-D, ZR-75) and HR-(MDA-MB-231) cells by transport studies conducted in the presence or absence of specific inhibitors. Amongst all the transporters and enzymes, OATPs and STS have significantly (p < 0.0001) higher expression in HR+ tumour sections with highest target signals obtained from the tumour regions of the tissues. Specific OATP-mediated E3S uptake and STS-mediated metabolism were also observed in all HR+ breast cancer cells. These observations suggest the potential of OATPs as novel molecular targets for HR+ breast cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. National Cancer Institute Annual Report (2013) http://seer.cancer.gov/statfacts/html/breast.html

  2. Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA (2007) The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. doi:10.1056/NEJMsr070105

    PubMed  Google Scholar 

  3. Linden HM, Mankoff DA (2010) Breast cancer and hormonal stimulation: is glycolysis the first sign of response? J Nucl Med 51:1663–1664. doi:10.2967/jnumed.110.078329

    Article  PubMed  Google Scholar 

  4. Anderson WF, Chatterjee N, Ershler WB, Brawley OW (2002) Estrogen receptor breast cancer phenotypes in the surveillance, epidemiology, and end results database. Breast Cancer Res Treat 76:27–36

    Article  CAS  PubMed  Google Scholar 

  5. Pasqualini JR, Chetrite GS (2005) Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer. J Steroid Biochem Mol Biol 93:221–236. doi:10.1016/j.jsbmb.2005.02.007

    Article  CAS  PubMed  Google Scholar 

  6. Geisler J (2003) Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol 86:245–253

    Article  CAS  PubMed  Google Scholar 

  7. Van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH (1985) Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res 45:2900–2906

    PubMed  Google Scholar 

  8. Kendall A, Folkerd EJ, Dowsett M (2007) Influences on circulating oestrogens in postmenopausal women: relationship with breast cancer. J Steroid Biochem Mol Biol 103:99–109

    Article  CAS  PubMed  Google Scholar 

  9. Santner SJ, Leszczynski D, Wright C, Manni A, Feil PD, Santen RJ (1986) Estrone sulfate: a potential source of estradiol in human breast cancer tissues. Breast Cancer Res Treat 7:35–44

    Article  CAS  PubMed  Google Scholar 

  10. Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72:23–27

    Article  CAS  PubMed  Google Scholar 

  11. Pasqualini JR, Chetrite G, Blacker C, Feinstein MC, Delalonde L, Talbi M, Maloche C (1996) Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab 81:1460–1464

    CAS  PubMed  Google Scholar 

  12. Buxhofer-Ausch V, Secky L, Wlcek K, Svoboda M, Kounnis V, Briasoulis E, Tzakos AG, Jaeger W, Thalhammer T (2013) Tumor-specific expression of organic anion-transporting polypeptides: transporters as novel targets for cancer therapy. J Drug Deliv 2013:863539. doi:10.1155/2013/863539

    Article  PubMed Central  PubMed  Google Scholar 

  13. Banerjee N, Allen C, Bendayan R (2012) Differential role of organic anion-transporting polypeptides in estrone-3-sulphate uptake by breast epithelial cells and breast cancer cells. J Pharmacol Exp Ther 342:510–519. doi:10.1124/jpet.112.192344

    Article  CAS  PubMed  Google Scholar 

  14. Hagenbuch B, Meier PJ (2004) Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch 447:653–665

    Article  CAS  PubMed  Google Scholar 

  15. Miki Y, Suzuki T, Kitada K, Yabuki N, Shibuya R, Moriya T, Ishida T, Ohuchi N, Blumberg B, Sasano H (2006) Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res 66:535–542

    Article  CAS  PubMed  Google Scholar 

  16. Meyer Zu, Schwabedissen HE, Tirona RG, Yip CS, Ho RH, Kim RB (2008) Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res 68:9338–9347

    Article  Google Scholar 

  17. Pizzagalli F, Varga Z, Huber RD, Folkers G, Meier PJ, St-Pierre MV (2003) Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab 88:3902–3912

    Article  CAS  PubMed  Google Scholar 

  18. Kindla J, Rau TT, Jung R, Fasching PA, Strick R, Stoehr R, Hartmann A, Fromm MF, Konig J (2011) Expression and localization of the uptake transporters OATP2B1, OATP3A1 and OATP5A1 in non-malignant and malignant breast tissue. Cancer Biol Ther 11:584–591

    Article  CAS  PubMed  Google Scholar 

  19. Pasqualini JR, Chetrite G, Nguyen BL, Maloche C, Delalonde L, Talbi M, Feinstein MC, Blacker C, Botella J, Paris J (1995) Estrone sulfate-sulfatase and 17 beta-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence. J Steroid Biochem Mol Biol 53:407–412

    Article  CAS  PubMed  Google Scholar 

  20. Conrad S, Kauffmann HM, Ito K, Leslie EM, Deeley RG, Schrenk D, Cole SP (2002) A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance. Pharmacogenetics 12:321–330

    Article  CAS  PubMed  Google Scholar 

  21. Imai Y, Asada S, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y (2003) Breast cancer resistance protein exports sulfated estrogens but not free estrogens. Mol Pharmacol 64:610–618. doi:10.1124/64.3.610

    Article  CAS  PubMed  Google Scholar 

  22. Fung AS, Jonkman J, Tannock IF (2012) Quantitative immunohistochemistry for evaluating the distribution of Ki67 and other biomarkers in tumor sections and use of the method to study repopulation in xenografts after treatment with paclitaxel. Neoplasia 14:324–334

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Huang W, Hennrick K, Drew S (2013) A colorful future of quantitative pathology: validation of Vectra technology using chromogenic multiplexed immunohistochemistry and prostate tissue microarrays. Hum Pathol 44:29–38. doi:10.1016/j.humpath.2012.05.009

    Article  CAS  PubMed  Google Scholar 

  24. Klapczynski M, Gagne GD, Morgan SJ, Larson KJ, Leroy BE, Blomme EA, Cox BF, Shek EW (2012) Computer-assisted imaging algorithms facilitate histomorphometric quantification of kidney damage in rodent renal failure models. J Pathol Inform. doi:10.4103/2153-3539.95456

    PubMed Central  PubMed  Google Scholar 

  25. Laurinavicius A, Laurinaviciene A, Ostapenko V, Dasevicius D, Jarmalaite S, Lazutka J (2012) Immunohistochemistry profiles of breast ductal carcinoma: factor analysis of digital image analysis data. Diagn Pathol. doi:10.1186/1746-1596-7-27

    PubMed Central  PubMed  Google Scholar 

  26. Konig J, Glaeser H, Keiser M, Mandery K, Klotz U, Fromm MF (2011) Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos 39:1097–1102. doi:10.1124/dmd.110.034991

    Article  PubMed  Google Scholar 

  27. Tirona RG, Leake BF, Wolkoff AW, Kim RB (2003) Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther 304:223–228. doi:10.1124/102.043026

    Article  CAS  PubMed  Google Scholar 

  28. Sandhu P, Lee W, Xu X, Leake BF, Yamazaki M, Stone JA, Lin JH, Pearson PG, Kim RB (2005) Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos 33:676–682. doi:10.1124/dmd.104.003244

    Article  CAS  PubMed  Google Scholar 

  29. Kis O, Zastre JA, Hoque MT, Walmsley SL, Bendayan R (2012) Role of drug efflux and uptake transporters in atazanavir intestinal permeability and drug–drug interactions. Pharm Res. doi:10.1007/s11095-012-0942

    PubMed  Google Scholar 

  30. Ronaldson PT, Ashraf T, Bendayan R (2010) Regulation of multidrug resistance protein 1 by tumor necrosis factor alpha in cultured glial cells: involvement of nuclear factor-kappaB and c-Jun N-terminal kinase signaling pathways. Mol Pharmacol 77:644–659

    Article  CAS  PubMed  Google Scholar 

  31. Purohit A, Chander SK, Woo LW, Parsons MF, Jhalli R, Potter BV, Reed MJ (2008) Inhibition of steroid sulphatase activity via the percutaneous route: a new option for breast cancer therapy. Anticancer Res 28:1517–1523

    CAS  PubMed  Google Scholar 

  32. Nakata T, Takashima S, Shiotsu Y, Murakata C, Ishida H, Akinaga S, Li PK, Sasano H, Suzuki T, Saeki T (2003) Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients. J Steroid Biochem Mol Biol 86:455–460

    Article  CAS  PubMed  Google Scholar 

  33. Suzuki T, Miki Y, Nakata T, Shiotsu Y, Akinaga S, Inoue K, Ishida T, Kimura M, Moriya T, Sasano H (2003) Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma. J Steroid Biochem Mol Biol 86:449–454

    Article  CAS  PubMed  Google Scholar 

  34. Imai Y, Ishikawa E, Asada S, Sugimoto Y (2005) Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2. Cancer Res 65:596–604

    Article  CAS  PubMed  Google Scholar 

  35. Imai Y, Tsukahara S, Ishikawa E, Tsuruo T, Sugimoto Y (2002) Estrone and 17beta-estradiol reverse breast cancer resistance protein-mediated multidrug resistance. Jpn J Cancer Res 93:231–235

    Article  CAS  PubMed  Google Scholar 

  36. Filipits M, Pohl G, Rudas M, Dietze O, Lax S, Grill R, Pirker R, Zielinski CC, Hausmaninger H, Kubista E, Samonigg H, Jakesz R (2005) Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. doi:10.1200/JCO.2005.03.033

    PubMed  Google Scholar 

  37. Rudas M, Filipits M, Taucher S, Stranzl T, Steger GG, Jakesz R, Pirker R, Pohl G (2003) Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. Breast Cancer Res Treat 81:149–157. doi:10.1023/1025751631115

    Article  CAS  PubMed  Google Scholar 

  38. Banerjee N, Fonge H, Mikhail A, Reilly RM, Bendayan R, Allen C (2013) Estrone-3-sulphate, a potential novel ligand for targeting breast cancers. PLoS One 8:e64069. doi:10.1371/0064069

    Article  PubMed Central  PubMed  Google Scholar 

  39. Maeda T, Irokawa M, Arakawa H, Kuraoka E, Nozawa T, Tateoka R, Itoh Y, Nakanishi T, Tamai I (2010) Uptake transporter organic anion transporting polypeptide 1B3 contributes to the growth of estrogen-dependent breast cancer. J Steroid Biochem Mol Biol 122:180–185. doi:10.1016/j.jsbmb.2010.06.014

    Article  CAS  PubMed  Google Scholar 

  40. Nozawa T, Suzuki M, Takahashi K, Yabuuchi H, Maeda T, Tsuji A, Tamai I (2004) Involvement of estrone-3-sulfate transporters in proliferation of hormone-dependent breast cancer cells. J Pharmacol Exp Ther 311:1032–1037. doi:10.1124/104.071522

    Article  CAS  PubMed  Google Scholar 

  41. Nozawa T, Suzuki M, Yabuuchi H, Irokawa M, Tsuji A, Tamai I (2005) Suppression of cell proliferation by inhibition of estrone-3-sulfate transporter in estrogen-dependent breast cancer cells. Pharm Res 22:1634–1641. doi:10.1007/s11095-005-7096-0

    Article  CAS  PubMed  Google Scholar 

  42. Wlcek K, Svoboda M, Thalhammer T, Sellner F, Krupitza G, Jaeger W (2008) Altered expression of organic anion transporter polypeptide (OATP) genes in human breast carcinoma. Cancer Biol Ther 7(1450–1455):6282

    Google Scholar 

  43. Suzuki M, Ishida H, Shiotsu Y, Nakata T, Akinaga S, Takashima S, Utsumi T, Saeki T, Harada N (2009) Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients. J Steroid Biochem Mol Biol 113:195–201. doi:10.1016/j.jsbmb.2008.12.008

    Article  CAS  PubMed  Google Scholar 

  44. Howell A, Bundred NJ, Cuzick J, Allred DC, Clarke R (2008) Response and resistance to the endocrine prevention of breast cancer. Adv Exp Med Biol 617:201–211. doi:10.1007/978-0-387-69080-3_19

    Article  CAS  PubMed  Google Scholar 

  45. Nicholson RI, Johnston SR (2005) Endocrine therapy—current benefits and limitations. Breast Cancer Res Treat 93(Suppl 1):S3–S10. doi:10.1007/s10549-005-9036-4

    Article  CAS  PubMed  Google Scholar 

  46. Lumachi F, Luisetto G, Basso SM, Basso U, Brunello A, Camozzi V (2011) Endocrine therapy of breast cancer. Curr Med Chem 18:513–522

    Article  CAS  PubMed  Google Scholar 

  47. Lumachi F, Brunello A, Maruzzo M, Basso U, Basso SM (2013) Treatment of estrogen receptor-positive breast cancer. Curr Med Chem 20:596–604

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors acknowledge Dr. Md. Tozammel Hoque for his help with the cell line transient transfection studies and Dr. Fei–Fei Liu for her excellent scientific advice and for serving as the Principal Investigator on the Research Ethics Board (REB) Tissue application. This research was supported by Internal University of Toronto funds allocated to Dr. Reina Bendayan and Dr. Christine Allen. Nilasha Banerjee is a recipient of the CIHR- Bio-Therapeutics Strategic Training doctoral fellowship and the Canadian Breast Cancer Foundation-Ontario region doctoral fellowship.

Conflict of interest

No conflicts of interest were identified.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, M5S 3M2, Canada

    Nilasha Banerjee, Christine Allen & Reina Bendayan

  2. Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Naomi Miller

Authors
  1. Nilasha Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naomi Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reina Bendayan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reina Bendayan.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 456 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Banerjee, N., Miller, N., Allen, C. et al. Expression of membrane transporters and metabolic enzymes involved in estrone-3-sulphate disposition in human breast tumour tissues. Breast Cancer Res Treat 145, 647–661 (2014). https://doi.org/10.1007/s10549-014-2990-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-2990-y

Keywords

Search

Navigation