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Thyroid hormone receptor α in breast cancer: prognostic and therapeutic implications

  • Epidemiology
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Abstract

We determined the expression of two transcriptional variants of thyroid hormone receptor alpha (THRα1 and THRα2) in samples from a cohort of breast cancer patients and correlated expression levels with survival. 130 women who were diagnosed with invasive breast carcinoma between 2007 and 2008 were included. Representative sections of their tumours were analyzed in triplicate on a tissue microarray for expression of THRα1 and THRα2 by immunohistochemistry. The prognostic significance of THRα1 and THRα2 expression was assessed using Kaplan–Meier survival analyses, adjusted for known prognostic factors. Seventy-four percent of tumours had high expression of THRα1 (Allred score ≥6) and 40 % had high expression of THRα2. Expression of THRα2 correlated positively with ER expression (p < 0.001) and with PR expression (p < 0.001), but negatively with HER2 expression (p = 0.018). Patients with low THRα2 expression had inferior 5-year overall survival (75.3 %) compared to those with high expression (91.7 %; p = 0.06). In a multivariate model, high THRα2 expression was a significant and independent prognosticator of improved overall survival (HR = 0.84; 95 % CI 0.71–0.98). Many breast tumours express THRα2 at high levels and these patients experience improved survival. Thyroid hormone signalling may be important in a proportion of breast cancers and THRα2 expression may be a regulator of signalling in this pathway.

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References

  1. Moeller LC, Fuhrer D (2013) Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr-Relat Cancer 20:R19–R29

    Article  CAS  PubMed  Google Scholar 

  2. Brent GA (2012) Mechanisms of thyroid hormone action. J Clin Invest 122(9):3035–3043

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Katz D, Reginato MJ, Lazar MA (1995) Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation. Mol Cell Biol 15(5):2341–2348

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Alvarado-Pisani AR, Chacon RS, Betancourt LJ et al (1986) Thyroid hormone receptors in human breast cancer: effect of thyroxine administration. Anticancer Res 6:1347–1351

    CAS  PubMed  Google Scholar 

  5. Cestari SH, Figueiredo NB, Conde SJ, Clara S, Katayama MLH et al (2009) Influence of estradiol and triiodothyronine on breast cancer cell lines proliferation and expression of estrogen and thyroid hormone receptors. Arq Bras Endocrinol Metabol 53:859–864

    Article  PubMed  Google Scholar 

  6. Hall LC, Salazar EP, Kane SR, Liu N (2008) Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol 109:57–66

    Article  CAS  PubMed  Google Scholar 

  7. Martinez MB, Ruan M, Fitzpatrick LA (2000) Altered response to thyroid hormones by prostate and breast cancer cells. Cancer Chemother Pharmacol 45:93–201

    Article  CAS  PubMed  Google Scholar 

  8. Nogueira CR, Brentani MM (1996) Triiodothyronine mimics the effects of estrogen in breast cancer cell lines. J Steroid Biochem Mol Biol 59:271–279

    Article  CAS  PubMed  Google Scholar 

  9. Chassande O (2003) Do unliganded thyroid hormone receptors have physiological functions? J Mol Endocrinol 31:9–20

    Article  CAS  PubMed  Google Scholar 

  10. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K et al (2010) Towards a knowledge-based human protein atlas. Nat Biotechnol 28(12):1248–1250

    Article  CAS  PubMed  Google Scholar 

  11. The cancer genome atlas data portal. National Institute of Health. Retrieved 2 July 2014

  12. Iberiro RCJ, Apriletti JW, Wagner RL, Feng W, Kushner PJ et al (1998) X-ray crystallographic and functional studies of thyroid hormone receptor. J Steroid Biochem Mol Biol 65(1):133–141

    Google Scholar 

  13. THRA thyroid hormone receptor, alpha. National Centre for Biotechnology Information. http://www.ncbi.nlm.nih.gov/gene/7067. Accessed 15 July 2014

  14. Lazar J, Desvergne B, Zimmerman E, Zimmer DB, Magnuson MA et al (1994) A role for intronic sequences on expression of thyroid hormone receptor α gene. J Biol Chem 269(32):20352–20359

    CAS  PubMed  Google Scholar 

  15. Mitsuhashi T, Tennyson GE, Nikodem VM (1988) Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. Proc Natl Acad Sci USA 85(16):5804–5808

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lazar MA, Hoin RA, Darling DS, Chin WW (1988) Identification of a rat c-erbA alpha-related protein which binds deoxyribonucleic acid but does not bind thyroid hormone. Mol Endocrinol 2:893–901

    Article  CAS  PubMed  Google Scholar 

  17. Izumo S, Mahdavi V (1988) Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially active myosin HC gene transcription. Nature 334(6182):539–542

    Article  CAS  PubMed  Google Scholar 

  18. Conde I, Paniagua R, Zamora J, Blánquez MJ, Fraile B et al (2006) Influence of thyroid hormone receptors on breast cancer cell proliferation. Ann Oncol 17:60–64

    Article  CAS  PubMed  Google Scholar 

  19. Ditch N, Toth B, Himsl I, Lenhard M, Ochsenkuhn R, Friese K, Mayr D, Jeschke U (2013) Thyroid hormone receptor (TR) alpha and TRbeta expression in breast cancer. Histol Histopathol 28:227–237

    Google Scholar 

  20. Silva JM, Dominguez G, Gonzalez-Sancho J, Garcia JM, Silva J, Garcia-Andrade C, Navarro A, Munoz A, Bonilla F (2002) Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene 21:4307–4316

    Article  CAS  PubMed  Google Scholar 

  21. Smallridge RC, Latham KR (1980) Nuclear thyroid hormone receptor in human breast tumours. Clin Res 28:421

    Google Scholar 

  22. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mol Pathol 11(2):155–168

    CAS  Google Scholar 

  23. Dinda S, Sanchez A, Moudgil V (2002) Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Oncogene 21(5):5761–5768

    Article  Google Scholar 

  24. Lamy P-J, Fina F, Bascoul-Mollevi C, Laberenne A-C, Martin P-M et al (2011) Quantification and clinical relevance of gene amplification at chromosome 17q12-q21in human epidermal growth factor receptor 2-amplified breast cancers. Breast Cancer Res 13:R15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Vasudevan N, Koibuchi N, Chin WW, Pfaff DW (2001) Differential crosstalk between estrogen receptor (ER)alpha and ERbeta and the thyroid hormone receptor isoforms results in flexible regulation of the consensus ERE. Brain Res Mol Brain Res 95:9–17

    Article  CAS  PubMed  Google Scholar 

  26. Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA et al (2003) Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study. Anticancer Res 23:617–626

    CAS  PubMed  Google Scholar 

  27. Hercbergs A (1999) Spontaneous remission of cancer- a thyroid hormone dependent phenomenon? Anticancer Res 19:4839–4844

    CAS  PubMed  Google Scholar 

  28. Hercbergs A, Johnson RE, Ashur-Fabian O, Garfield DH, Davis PJ (2014) Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study. Oncologist 2014-0308 (Epub ahead of print)

  29. Gu G, Covington KR, Rechoum Y, Fuqua SAW (2012) Restoration of receptor α in triple negative breast cancer via targeting of thyroid hormone. Cancer Res 72(24 Suppl):49

    Google Scholar 

  30. Sabnis GJ, Goloubeva O, Chumsri S, Nyguyen N, Sukumar S, Brodie AMH (2011) Functional activation of the estrogen-α and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumours to letrozole. Cancer Res 71(5):1893–1903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Angelousi AG, Anagnostou VK, Stamatakos MK, Georgiopoulos GA, Kontzoglou KC (2012) Primary HT and risk for breast cancer: a systematic review and meta-analysis. Eur J Endocrinol 166:373–381

    Article  CAS  PubMed  Google Scholar 

  32. Davis PJ, Lin Y-Y, Mousa SA, Luidens MK, Hercbergs AA, Wehling M, Davis FB (2011) Overlapping nongenomic and genomic actions of thyroid hormone and steroids. Steroids 76:829–833

    CAS  PubMed  Google Scholar 

  33. Tang HY, Lin HY, Zhang S, Davis FB, Davis PJ (2004) Thyroid hormone causes mitogen-activated protein kinase-dependent phosphorylation of the nuclear estrogen receptor. Endocrinology 145:3265–3272

    Article  CAS  PubMed  Google Scholar 

  34. Furuya F, Shimura H, Yamashita S, Endo T, Kobayashi T (2010) Liganded thyroid hormone receptor-α enhances proliferation of pancreatic β-cells. J Biol Chem 285:24477–24486

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Hellevik AI, Asvold BO, Bjoro T, Romundstad PR, Nilsen TIL, Vatten LJ (2009) Thyroid function and cancer risk: a prospective population study. Cancer Epidemiol Biomark Prev 18:570–574

    Article  CAS  Google Scholar 

  36. Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Malm J et al (2010) Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 12(3):R33

    Article  PubMed Central  PubMed  Google Scholar 

  37. De Sibio MT, de Oliveira M, Moretto FC, Olimpio RM, Conde SJ et al (2014) Triiodothyronine and breast cancer. World J Clin Oncol 5(3):503–508

    Article  PubMed Central  PubMed  Google Scholar 

  38. Sandhu MK, Brezden-Masley C, Lipscombe LL, Zagorski B, Booth GL (2009) Autoimmune hypothyroidism and breast cancer in the elderly. Breast Cancer Res Treat 115(3):635–641

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was funded by the Hamilton Health Sciences New Investigator Fund. We would like to thank Tanja Thurn for her meticulous work in optimizing the immunohistochemical studies, Ying Wu for preparing the tissue microarrays and Marissa Laureano for creating the illustrations.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medicine, University of Toronto, 27 King’s College Cir, Toronto, ON, M5S 1A1, Canada

    Katarzyna J. Jerzak, Kathleen I. Pritchard & Steven A. Narod

  2. Department of Oncology, Juravinski Cancer Centre, 699 Concession St, Hamilton, ON, L8V 5C2, Canada

    Jessica Cockburn, Gregory R. Pond, Sukhbinder K. Dhesy-Thind & Anita Bane

  3. Department of Public Health Sciences, University of Toronto, 155 College Street, 6th floor, Toronto, ON, M5T 3M7, Canada

    Kathleen I. Pritchard & Steven A. Narod

  4. Familial Breast Cancer Research Unit, Women’s College Research Institute, 790 Bay St., 7th floor, Toronto, ON, M5G1N8, Canada

    Steven A. Narod

  5. Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada

    Anita Bane

Authors
  1. Katarzyna J. Jerzak
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  2. Jessica Cockburn
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Correspondence to Steven A. Narod.

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Jerzak, K.J., Cockburn, J., Pond, G.R. et al. Thyroid hormone receptor α in breast cancer: prognostic and therapeutic implications. Breast Cancer Res Treat 149, 293–301 (2015). https://doi.org/10.1007/s10549-014-3235-9

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  • DOI: https://doi.org/10.1007/s10549-014-3235-9

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