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Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen

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Abstract

Transferrin receptor (CD71) is involved in the cellular uptake of iron and is expressed on cells with high proliferation. It may be implicated in promoting the growth of endocrine resistant phenotypes within ER+/luminal-like breast cancer. We used a panel of in vitro cell models of acquired resistance to tamoxifen (TAMR), Faslodex (FASR) or severe oestrogen deprivation (MCF-7X) and the ER+ luminal MCF-7 parental line to determine CD71 mRNA expression and to study transferrin (Tf) effects on in vitro tumour growth and its inhibition. Furthermore, CD71 protein expression was assessed in a well-characterized series of patients with invasive breast carcinoma using tissue microarrays. Our results demonstrated a striking elevation of CD71 in all cell models of acquired resistance. Exogenous Tf significantly promoted growth in MCF-7-X and MCF-7 cells but more so in MCF-7-X; this growth was significantly reduced by Faslodex (FAS) or a phosphoinositide-3 kinase inhibitor (LY294002). Increased CD71 expression was associated with poor NPI score, tumour proliferation, basal CKs, p53, EGFR, HER2, steroid receptor negativity and shortened breast cancer specific survival (P < 0.001). On multivariate analysis, CD71 was found to be an independent prognostic factor in the ER+ cohort of patients. In conclusion, therapies of current interest in breast cancer (e.g. FAS, PI3K-inhibitors) appear able to partially impact on transferrin/CD71-promoted growth, but further investigation of this important mitogenic mechanism may assist in designing new therapeutic strategies to target highly proliferative, endocrine resistant breast cancers. CD71 appears to be a candidate marker of a subgroup of ER+/luminal-like breast cancer characterised by poor outcome and resistance to tamoxifen.

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References

  1. Ponka P, Lok CN (1999) The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 31:1111–1137. doi:10.1016/S1357-2725(99)00070-9

    Article  CAS  PubMed  Google Scholar 

  2. Richardson DR, Ponka P (1997) The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim et Biophys Acta (BBA)-Rev Biomembr 1331:1–40

    CAS  Google Scholar 

  3. Daniels TR, Delgado T, Rodriguez JA, Helguera G, Penichet ML (2006) The transferrin receptor part I: biology and targeting with cytotoxic antibodies for the treatment of cancer. Clin Immunol 121:144–158. doi:10.1016/j.clim.2006.06.010

    Article  CAS  PubMed  Google Scholar 

  4. Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M (1981) Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc Natl Acad Sci USA 78:4515–4519. doi:10.1073/pnas.78.7.4515

    Article  CAS  PubMed  Google Scholar 

  5. Dowlati A, Loo M, Bury T, Fillet G, Beguin Y (1997) Soluble and cell-associated transferrin receptor in lung cancer. Br J Cancer 75:1802–1806

    CAS  PubMed  Google Scholar 

  6. Carbognani P, Rusca M, Romani A, Spaggiari L, Cattelani L, Solli P et al (1996) Transferrin receptor expression in nonsmall cell lung cancer—histopathologic and clinical correlates. Cancer 78:178–179. doi:10.1002/(SICI)1097-0142(19960701)78:1<178::AID-CNCR25>3.0.CO;2-W

    Article  CAS  PubMed  Google Scholar 

  7. Lanson B, Drenou B, Gueret P, Amiot L, Bernard M, Dauriac C et al (1997) Prognostic value of CD71 expression in mantle cell lymphoma. Exp Hematol 25:401

    Google Scholar 

  8. Prost AC, Menegaux F, Langlois P, Vidal JM, Koulibaly M, Jost JL et al (1998) Differential transferrin receptor density in human colorectal cancer: a potential probe for diagnosis and therapy. Int J Oncol 13:871–875

    CAS  PubMed  Google Scholar 

  9. Ryschich E, Huszty G, Knaebel HP, Hartel M, Buchler MW, Schmidt J (2004) Transferrin receptor is a marker of malignant phenotype in human pancreatic cancer and in neuroendocrine carcinoma of the pancreas. Eur J Cancer 40:1418–1422. doi:10.1016/j.ejca.2004.01.036

    Article  CAS  PubMed  Google Scholar 

  10. Tonik SE, Shindelman JE, Sussman HH (1986) Transferrin receptor is inversely correlated with estrogen-receptor in breast-cancer. Breast Cancer Res Treat 7:71–76. doi:10.1007/BF01806791

    Article  CAS  PubMed  Google Scholar 

  11. Wrba F, Ritzinger E, Reiner A, Holzner JH (1986) Transferrin receptor (Trfr) expression in breast-carcinoma and its possible relationship to prognosis—an immunohistochemical study. Virchows Arch-Pathol Anat Histopathol 410:69–73

    Article  CAS  Google Scholar 

  12. Dai J, Jian J, Bosland M, Frenkel K, Bernhardt G, Huang X (2008) Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status. Breast 17:172–179. doi:10.1016/j.breast.2007.08.009

    Article  PubMed  Google Scholar 

  13. Cavanaugh PG, Jia LB, Zou YY, Nicolson GL (1999) Transferrin receptor overexpression enhances transferrin responsiveness and the metastatic growth of a rat mammary adenocarcinoma cell line. Breast Cancer Res Treat 56:203–217. doi:10.1023/A:1006209714287

    Article  CAS  PubMed  Google Scholar 

  14. Staka CM, Nicholson RI, Gee JMW (2005) Acquired resistance to oestrogen deprivation: role for growth factor signalling kinases/oestrogen receptor cross-talk revealed in new MCF-7X model. Endocr Relat Cancer 12:S85–S97. doi:10.1677/erc.1.01006

    Article  CAS  PubMed  Google Scholar 

  15. Nicholson RI, Hutcheson IR, Hiscox SE, Knowlden JM, Giles M, Barrow D et al (2005) Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer. Endocr Relat Cancer 12:S29–S36. doi:10.1677/erc.1.00991

    Article  CAS  PubMed  Google Scholar 

  16. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JMW, Harper ME et al (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044. doi:10.1210/en.2002-220620

    Article  CAS  PubMed  Google Scholar 

  17. Hiscox S, Jordan NJ, Jiang W, Harper M, McClelland R, Smith C et al (2006) Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions. Endocr Relat Cancer 13:1085–1099. doi:10.1677/erc.1.01270

    Article  CAS  PubMed  Google Scholar 

  18. Knowlden JM, Gee JM, Bryant S, McClelland RA, Manning DL, Mansel R et al (1997) Use of reverse transcription-polymerase chain reaction methodology to detect estrogen-regulated gene expression in small breast cancer specimens. Clin Cancer Res 3:2165–2172

    CAS  PubMed  Google Scholar 

  19. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JFR et al (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116:340–350. doi:10.1002/ijc.21004

    Article  CAS  PubMed  Google Scholar 

  20. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast-cancer. 1. The value of histological grade in breast-cancer—experience from a large study with long-term follow-up. Histopathology 19:403–410. doi:10.1111/j.1365-2559.1991.tb00229.x

    Article  CAS  PubMed  Google Scholar 

  21. Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham prognostic index in primary breast-cancer. Breast Cancer Res Treat 22:207–219. doi:10.1007/BF01840834

    Article  CAS  PubMed  Google Scholar 

  22. Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW et al (2004) Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer 91:1532–1542. doi:10.1038/sj.bjc.6602184

    Article  CAS  PubMed  Google Scholar 

  23. Rakha EA, El Rehim DA, Pinder SE, Lewis SA, Ellis IO (2005) E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance. Histopathology 46:685–693. doi:10.1111/j.1365-2559.2005.02156.x

    Article  CAS  PubMed  Google Scholar 

  24. Rakha EA, El-Sayed ME, Green AR, Paish EC, Lee AHS, Ellis IO (2007) Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression. Histopathology 50:434–438. doi:10.1111/j.1365-2559.2007.02638.x

    Article  CAS  PubMed  Google Scholar 

  25. Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ et al (2008) Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur J Cancer 44:73–83. doi:10.1016/j.ejca.2007.10.009

    Article  PubMed  Google Scholar 

  26. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847. doi:10.1038/nm0798-844

    Article  CAS  PubMed  Google Scholar 

  27. Habashy HO, Powe DG, Rakha EA, Ball G, Paish C, Gee J et al (2008) Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance. Eur J Cancer 44:1541–1551. doi:10.1016/j.ejca.2008.04.020

    Article  CAS  PubMed  Google Scholar 

  28. McCarty KS, Miller LS, Cox EB, Konrath J, McCarty KS (1985) Estrogen-receptor analyses—correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721

    PubMed  Google Scholar 

  29. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874. doi:10.1073/pnas.191367098

    Article  CAS  PubMed  Google Scholar 

  30. Naderi A, Teschendorff AE, Barbosa-Morais NL, Pinder SE, Green AR, Powe DG et al (2006) A gene-expression signature to predict survival in breast cancer across independent data sets. Oncogene 26:1507–1516. doi:10.1038/sj.onc.1209920

    Article  PubMed  Google Scholar 

  31. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  32. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423. doi:10.1073/pnas.0932692100

    Article  CAS  PubMed  Google Scholar 

  33. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398. doi:10.1073/pnas.1732912100

    Article  CAS  PubMed  Google Scholar 

  34. West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R et al (2001) Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci USA 98:11462–11467. doi:10.1073/pnas.201162998

    Article  CAS  PubMed  Google Scholar 

  35. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874. doi:10.1073/pnas.191367098

    Article  CAS  PubMed  Google Scholar 

  36. Inoue T, Cavanaugh PG, Steck PA, Brunner N, Nicolson GL (1993) Differences in transferrin response and numbers of transferrin receptors in rat and human mammary-carcinoma lines of different metastatic potentials. J Cell Physiol 156:212–217. doi:10.1002/jcp.1041560128

    Article  CAS  PubMed  Google Scholar 

  37. Yang DC, Jiang XP, Elliott RL, Head JF (2001) Inhibition of growth of human breast carcinoma cells by an antisense oligonucleotide targeted to the transferrin receptor gene. Anticancer Res 21:1777–1787

    CAS  PubMed  Google Scholar 

  38. Peng JL, Wu S, Zhao XP, Wang M, Li WH, Shen X et al (2007) Downregulation of transferrin receptor surface expression by intracellular antibody. Biochem Biophys Res Commun 354:864–871. doi:10.1016/j.bbrc.2007.01.052

    Article  CAS  PubMed  Google Scholar 

  39. Jones DT, Trowbridge IS, Harris AL (2006) Effects of transferrin receptor blockade on cancer cell proliferation and hypoxia-inducible factor function and their differential regulation by ascorbate. Cancer Res 66:2749–2756. doi:10.1158/0008-5472.can-05-3857

    Article  CAS  PubMed  Google Scholar 

  40. Jess TJ, Belham CM, Thomson FJ, Scott PH, Plevin RJ, Gould GW (1996) Phosphatidylinositol 3′-kinase, but not p70 ribosomal S6 kinase, is involved in membrane protein recycling: wortmannin inhibits glucose transport and downregulates cell-surface transferrin receptor numbers independently of any effect on fluid-phase endocytosis in fibroblasts. Cell Signal 8:297–304. doi:10.1016/0898-6568(96)00054-X

    Article  CAS  PubMed  Google Scholar 

  41. Rakha EA, El-Rehim DA, Paish C, Green AR, Lee AHS, Robertson JF et al (2006) Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur J Cancer 42:3149–3156. doi:10.1016/j.ejca.2006.08.015

    Article  CAS  PubMed  Google Scholar 

  42. Potemski P, Kusinska R, Watala C, Pluciennik E, Bednarek AK, Kordek R (2005) Prognostic relevance of basal cytokeratin expression in operable breast cancer. Oncology 69:478–485. doi:10.1159/000090986

    Article  PubMed  Google Scholar 

  43. van de Rijn M, Perou CM, Tibshirani R, Haas P, Kallioniemi C, Kononen J et al (2002) Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome. Am J Pathol 161:1991–1996

    PubMed  Google Scholar 

  44. Tsutsui S, Ohno S, Murakami S, Kataoka A, Kinoshita J, Hachitanda Y (2002) EGFR, c-erbB2 and p53 protein in the primary lesions and paired metastatic regional lymph nodes in breast cancer. Eur J Surg Oncol 28:383–387. doi:10.1053/ejso.2002.1259

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the ministry of high education (Egypt) for funding HO Habashy and M Aleskandarany, Breast Cancer Campaign for funding A Green, and the John and Lucille van Geest foundation for providing support to G Ball. Thanks to the Tenovus Charity for supporting JMW Gee and C Staka

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Authors and Affiliations

  1. Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK

    Hany Onsy Habashy, Desmond G. Powe, Emad A. Rakha, Andrew R. Green, Mohammed Aleskandarany, E. Claire Paish & Ian O. Ellis

  2. The Breast Institute, Nottingham University Hospitals NHS Trust, Nottingham, UK

    R. Douglas Macmillan

  3. School of Science and Technology, Nottingham Trent University, Nottingham, UK

    Graham Ball

  4. Welsh School of Pharmacy, Cardiff University, Cardiff, UK

    Cindy M. Staka, Robert I. Nicholson & Julia M. W. Gee

  5. Department of Histopathology, Mansoura University, Mansoura, Egypt

    Hany Onsy Habashy

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  1. Hany Onsy Habashy
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  2. Desmond G. Powe
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  3. Cindy M. Staka
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Correspondence to Ian O. Ellis.

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Habashy, H.O., Powe, D.G., Staka, C.M. et al. Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer Res Treat 119, 283–293 (2010). https://doi.org/10.1007/s10549-009-0345-x

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  • DOI: https://doi.org/10.1007/s10549-009-0345-x

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