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Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC)

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Abstract

Triple negative breast cancers express receptors for gonadotropin-releasing hormone (GnRH) in more than 50 % of the cases, which can be targeted with peptidic analogs of GnRH, such as triptorelin. The current study investigates cytotoxic activity of triptorelin as a monotherapy and in treatment combinations with chemotherapeutic agents and inhibitors of the PI3K and the ERK pathways in in vitro models of triple negative breast cancers (TNBC). GnRH receptor expression of TNBC cell lines MDA-MB-231 and HCC1806 was investigated. Cells were treated with triptorelin, chemotherapeutic agents (cisplatin, docetaxel, AEZS-112), PI3K/AKT inhibitors (perifosine, AEZS-129), an ERK inhibitor (AEZS-134), and dual PI3K/ERK inhibitor AEZS-136 applied as single agent therapies and in combinations. MDA-MB-231 and HCC1806 TNBC cells both expressed receptors for GnRH on messenger (m)RNA and protein level and were found sensitive to triptorelin with a respective median effective concentration (EC50) of 31.21 ± 0.21 and 58.50 ± 19.50. Synergistic effects occurred when triptorelin was combined with cisplatin. In HCC1806 cells, synergy occurred when triptorelin was applied with PI3K/AKT inhibitors perifosine and AEZS-129. In MDA-MB-231 cells, synergy was observed after co-treatment with triptorelin and ERK inhibitor AEZS-134 and dual PI3K/ERK inhibitor AEZS-136. GnRH receptors on TNBC cells can be used for targeted therapy of these cancers with GnRH agonist triptorelin. Treatment combinations based on triptorelin and PI3K and ERK inhibitors and chemotherapeutic agent cisplatin have synergistic effects in in vitro models of TNBC. If confirmed in vivo, clinical trials based on triptorelin and cisplatin could be quickly carried out, as triptorelin is FDA approved for other indications and known to be well tolerated.

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References

  1. De Laurentiis M, Cianniello D, Caputo R, Stanzione B, Arpino G, Cinieri S et al (2010) Treatment of triple negative breast cancer (TNBC): current options and future perspectives. Cancer Treat Rev 36(Suppl 3):S80–S86

    Article  PubMed  Google Scholar 

  2. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res: Off J Am Assoc Cancer Res 13:2329–2334

    Article  CAS  Google Scholar 

  3. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res: Off J Am Assoc Cancer Res 13:4429–4434

    Article  Google Scholar 

  4. Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32

    Article  CAS  PubMed  Google Scholar 

  5. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109:1721–1728

    Article  PubMed  Google Scholar 

  6. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA et al (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7:134

    Article  PubMed Central  PubMed  Google Scholar 

  7. Schally AV, Comaru-Schally AM, Nagy A, Kovacs M, Szepeshazi K, Plonowski A et al (2001) Hypothalamic hormones and cancer. Front Neuroendocrinol 22:248–291

    Article  CAS  PubMed  Google Scholar 

  8. Engel JB, Schally AV (2007) Drug insight: clinical use of agonists and antagonists of luteinizing-hormone-releasing hormone. Nat Clin Pract Endocrinol Metab 3:157–167

    Article  CAS  PubMed  Google Scholar 

  9. Westphalen S, Kotulla G, Kaiser F, Krauss W, Werning G, Elsasser HP et al (2000) Receptor mediated antiproliferative effects of the cytotoxic LHRH agonist AN-152 in human ovarian and endometrial cancer cell lines. Int J Oncol 17:1063–1069

    CAS  PubMed  Google Scholar 

  10. Schally AV (1999) LH-RH analogues: I. Their impact on reproductive medicine. Gynecol Endocrinol Off J Int Soc Gynecol Endocrinol 13:401–409

    Article  CAS  Google Scholar 

  11. Engel JB, Schally AV, Dietl J, Rieger L, Honig A (2007) Targeted therapy of breast and gynecological cancers with cytotoxic analogues of peptide hormones. Mol Pharm 4:652–658

    Article  CAS  PubMed  Google Scholar 

  12. Schally AV, Nagy A (2003) New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin. Life Sci 72:2305–2320

    Article  CAS  PubMed  Google Scholar 

  13. Schally AV, Nagy A (2004) Chemotherapy targeted to cancers through tumoral hormone receptors. Trends Endocrinol Metab: TEM 15:300–310

    Article  CAS  PubMed  Google Scholar 

  14. Buchholz S, Seitz S, Schally AV, Engel JB, Rick FG, Szalontay L et al (2009) Triple-negative breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH) and respond to LHRH antagonist cetrorelix with growth inhibition. Int J Oncol 35:789–796

    CAS  PubMed  Google Scholar 

  15. Fost C, Duwe F, Hellriegel M, Schweyer S, Emons G, Grundker C (2011) Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. Oncol Rep 25:1481–1487

    CAS  PubMed  Google Scholar 

  16. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529

    Article  CAS  PubMed  Google Scholar 

  17. Huober J, Fasching PA, Hanusch C, Rezai M, Eidtmann H, Kittel K et al (2013) Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC) +/− bevacizumab—results of the randomised GeparQuinto study (GBG 44). Eur J Cancer 49:2284–2293

    Article  CAS  PubMed  Google Scholar 

  18. Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446

    Article  CAS  PubMed  Google Scholar 

  19. Forbes SA, Tang G, Bindal N, Bamford S, Dawson E, Cole C et al (2010) COSMIC (the catalogue of somatic mutations in cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res 38:D652–D657

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Engel JB, Schally AV, Buchholz S, Seitz S, Emons G, Ortmann O (2012) Targeted chemotherapy of endometrial, ovarian and breast cancers with cytotoxic analogs of luteinizing hormone-releasing hormone (LHRH). Arch Gynecol Obstet 286:437–442

    Article  CAS  PubMed  Google Scholar 

  21. Schally AV (1999) Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis. Peptides 20:1247–1262

    Article  CAS  PubMed  Google Scholar 

  22. Fister S, Schlotawa L, Gunthert AR, Emons G, Grundker C (2008) Increase of doxorubicin-induced apoptosis after knock-down of gonadotropin-releasing hormone receptor expression in human endometrial, ovarian and breast cancer cells. Gynecol Endocrinol 24:24–29

    Article  CAS  PubMed  Google Scholar 

  23. Emons G, Schulz KD (2000) Primary and salvage therapy with LH-RH analogues in ovarian cancer. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 153:83–94

  24. Ackermans PA, Solosko TA, Spencer EC, Gehman SE, Nammi K, Engel J et al (2012) A user-friendly integrated monitor-adhesive patch for long-term ambulatory electrocardiogram monitoring. J Electrocardiol 45:148–153

    Article  PubMed  Google Scholar 

  25. Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N (2009) Triple-negative breast cancer—current status and future directions. Ann Oncol: Off J Eur Soc Med Oncol / ESMO 20:1913–1927

    Article  CAS  Google Scholar 

  26. Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q et al (2010) Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol 28:1145–1153

    Article  CAS  Google Scholar 

  27. Wong E, Giandomenico CM (1999) Current status of platinum-based antitumor drugs. Chem Rev 99:2451–2466

    Article  CAS  PubMed  Google Scholar 

  28. Hernandez-Aya LF, Gonzalez-Angulo AM (2011) Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 16:404–414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Marty B, Maire V, Gravier E, Rigaill G, Vincent-Salomon A, Kappler M et al (2008) Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res: BCR 10:R101

    Article  PubMed Central  PubMed  Google Scholar 

  30. Lopez-Knowles E, O’Toole SA, McNeil CM, Millar EK, Qiu MR, Crea P et al (2010) PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer J Int du Cancer 126:1121–1131

    CAS  Google Scholar 

  31. Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689

    CAS  PubMed  Google Scholar 

  32. Garnett MJ, Marais R (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6:313–319

    Article  CAS  PubMed  Google Scholar 

  33. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  34. Schubbert S, Shannon K, Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295–308

    Article  CAS  PubMed  Google Scholar 

  35. Bartholomeusz C, Gonzalez-Angulo AM, Liu P, Hayashi N, Lluch A, Ferrer-Lozano J et al (2012) High ERK protein expression levels correlate with shorter survival in triple-negative breast cancer patients. Oncologist 17:766–774

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant by Deutsche Forschungsgemeinschaft (DFG) to JBE (Grant number: EN 434/3-1).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, University Medical Center Regensburg, 93053, Regensburg, Germany

    C. W. Kwok, O. Treeck, S. Buchholz, S. Seitz, O. Ortmann & J. B. Engel

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  1. C. W. Kwok
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  2. O. Treeck
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  3. S. Buchholz
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  4. S. Seitz
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  5. O. Ortmann
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  6. J. B. Engel
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Correspondence to J. B. Engel.

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Kwok, C.W., Treeck, O., Buchholz, S. et al. Receptors for luteinizing hormone-releasing hormone (GnRH) as therapeutic targets in triple negative breast cancers (TNBC). Targ Oncol 10, 365–373 (2015). https://doi.org/10.1007/s11523-014-0340-y

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  • DOI: https://doi.org/10.1007/s11523-014-0340-y

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