Original Article
Expression of sex hormone receptors in juvenile angiofibromas and antiproliferative effects of receptor modulators
Bernhard Schick MD,
Julia Dlugaiczyk MD,
Olaf Wendler PhD,
Corresponding Author
Bernhard Schick MD
Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
Corresponding author: B. Schick, Department of Otorhinolaryngology, Saarland University Medical Center, Kirrberger Strasse, Building no. 6, D-66421 Homburg/Saar, Germany. E-mail: [email protected]Search for more papers by this authorJulia Dlugaiczyk MD
Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
Search for more papers by this authorOlaf Wendler PhD
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Erlangen, Erlangen, Germany
Search for more papers by this authorBernhard Schick MD,
Julia Dlugaiczyk MD,
Olaf Wendler PhD,
Corresponding Author
Bernhard Schick MD
Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
Corresponding author: B. Schick, Department of Otorhinolaryngology, Saarland University Medical Center, Kirrberger Strasse, Building no. 6, D-66421 Homburg/Saar, Germany. E-mail: [email protected]Search for more papers by this authorJulia Dlugaiczyk MD
Department of Otorhinolaryngology, Saarland University Medical Center, Homburg/Saar, Germany
Search for more papers by this authorOlaf Wendler PhD
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Erlangen, Erlangen, Germany
Search for more papers by this authorAbstract
Background
Predilection of juvenile angiofibromas in adolescent boys has prompted the hypothesis of hormone-dependent tumor growth. However, knowledge on expression and function of sex hormone receptors in juvenile angiofibromas is still sparse and inconsistent.
Methods
Transcript and protein expression of sex hormone receptors in juvenile angiofibromas was studied by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) and immunohistology/fluorescence. A bromodeoxyuridine assay was used to assess the antiproliferative effects of flutamide (androgen receptor antagonist) and tamoxifen (estrogen receptor modulator).
Results
Significantly increased transcript levels were observed for androgen receptor, estrogen receptor α, follicle-stimulating hormone receptor, and luteinizing hormone receptor in juvenile angiofibromas versus the stroma of nasal mucosa. Estrogen receptor β and progesterone receptor mRNA levels were low and similar for both tissues. Estrogen receptor α protein was detected in juvenile angiofibroma tumors and mesenchymal cell lines. Flutamide and tamoxifen inhibited proliferation of cultured juvenile angiofibroma mesenchymal cells.
Conclusion
These findings contribute to the understanding of juvenile angiofibroma pathophysiology and offer novel therapeutic options. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1596–1603, 2014
REFERENCES
- 1 Martin H, Ehrlich HE, Abels JC. Juvenile nasopharyngeal angiofibroma. Ann Surg 1948; 127: 513–536.
- 2 Hulthen UL, Toremalm NG. Juvenile nasopharyngeal angiofibroma. J Otolaryngol 1976; 5: 55–63.
- 3 Farag MM, Ghanimah SE, Ragaie A, Saleem TH. Hormonal receptors in juvenile nasopharyngeal angiofibroma. Laryngoscope 1987; 97: 208–211.
- 4
Lee DA,
Rao BR,
Meyer JS,
Prioleau PG,
Bauer WC. Hormonal receptor determination in juvenile nasopharyngeal angiofibromas. Cancer 1980; 46: 547–551.
10.1002/1097-0142(19800801)46:3<547::AID-CNCR2820460321>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- 5 Antonelli AR, Cappiello J, Di Lorenzo D, Donajo CA, Nicolai P, Orlandini A. Diagnosis, staging, and treatment of juvenile nasopharyngeal angiofibromas (JNA). Laryngoscope 1987; 97: 1319–1325.
- 6 Brentani MM, Butugan O, Oshima CT, Torloni H, Paiva LJ. Multiple steroid receptors in nasopharyngeal angiofibromas. Laryngoscope 1989; 99: 398–401.
- 7 Gatalica Z. Immunohistochemical analysis of steroid hormone receptors in nasopharyngeal angiofibromas. Cancer Lett 1998; 127: 89–93.
- 8 Hwang HC, Mills SE, Patterson K, Gown AM. Expression of androgen receptors in nasopharyngeal angiofibroma: an immunohistochemical study of 24 cases. Mod Pathol 1998; 11: 1122–1126.
- 9 Montag AG, Tretiakova M, Richardson M. Steroid hormone receptor expression in nasopharyngeal angiofibromas. Consistent expression of estrogen receptor beta. Am J Clin Pathol 2006; 125: 832–837.
- 10 Liang J, Yi Z, Liang P. The nature of juvenile nasopharyngeal angiofibroma. Otolaryngol Head Neck Surg 2000; 123: 475–481.
- 11 Saylam G, Yücel OT, Sungur A, Onerci M. Proliferation, angiogenesis and hormonal markers in juvenile nasopharyngeal angiofibromas. Int J Pediatr Otorhinolaryngol 2006; 70: 227–234.
- 12 Ji Q, Chen P, Aoyoma C, Liu P. Increased expression of human luteinizing hormone/human chorionic gonadotropin receptor mRNA in human endometrial cancer. Mol Cell Probes 2002; 16: 269–275.
- 13 Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 2002; 23: 141–174.
- 14 Ziecik AJ, Kaczmarek MM, Blitek A, Kowalczyk AE, Li X, Rahman NA. Novel biological and possible applicable roles of LH/hCG receptor. Mol Cell Endocrinol 2007; 269: 51–60.
- 15 Hermann BP, Heckert LL. Transcriptional regulation of the FSH receptor: new perspectives. Mol Cell Endocrinol 2007; 260–262: 100–108.
- 16 Gartrell BA, Tsao CK, Galsky MD. The follicle-stimulating hormone receptor: a novel target in genitourinary malignancies. Urol Oncol 2012. [Epub ahead of print]
- 17 Wendler O, Dlugaiczyk J, Birk S, Schick B. Anti-proliferative effect of glucocorticoids on mesenchymal cells in juvenile angiofibromas. Head Neck 2012; 34: 1615–1621.
- 18 Schick B, Wemmert S, Jung V, Steudel WI, Montenarh M, Urbschat S. Genetic heterogeneity of the MYC oncogene in advanced juvenile angiofibromas. Cancer Genet Cytogenet 2006; 164: 25–31.
- 19 Andrews JC, Fisch U, Valavanis A, Aeppli U, Makek MS. The surgical management of extensive nasopharyngeal angiofibromas with the infratemporal fossa approach. Laryngoscope 1989; 99: 429–437.
- 20 Schick B, Wemmert S, Willnecker V, et al. Genome-wide copy number profiling using a 100K SNP array reveals novel disease-related genes BORIS and TSHZ1 in juvenile angiofibroma. Int J Oncol 2011; 39: 1143–1151.
- 21 Gramann M, Wendler O, Haeberle L, Schick B. Prominent collagen type VI expression in juvenile angiofibromas. Histochem Cell Biol 2009; 131: 155–164.
- 22 Hagen R, Romalo G, Schwab B, Hoppe F, Schweikert HU. Juvenile nasopharyngeal fibroma: androgen receptors and their significance for tumor growth. Laryngoscope 1994; 104: 1125–1129.
- 23 Pelletier G, Ren L. Localization of sex steroid receptors in human skin. Histol Histopathol 2004; 19: 629–636.
- 24 Ruffy MB, Kunnavatana SS, Koch RJ. Effects of tamoxifen on normal human dermal fibroblasts. Arch Facial Plast Surg 2006; 8: 329–332.
- 25 Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3: RESEARCH0034.
- 26 Schick B, Rippel C, Brunner C, Jung V, Plinkert PK, Urbschat S. Numerical sex chromosome aberrations in juvenile angiofibromas: genetic evidence for an androgen-dependent tumor? Oncol Rep 2003; 10: 1251–1255.
- 27 Silveira SM, Custódio Domingues MA, Butugan O, Brentani MM, Rogatto SR. Tumor microenvironmental genomic alterations in juvenile nasopharyngeal angiofibroma. Head Neck 2012; 34: 485–492.
- 28 Pawlowski JE, Ertel JR, Allen MO, et al. Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells. J Biol Chem 2002; 277: 20702–20710.
- 29 Abraham SC, Montgomery EA, Giardiello FM, Wu TT. Frequent beta-catenin mutations in juvenile nasopharyngeal angiofibromas. Am J Pathol 2001; 158: 1073–1078.
- 30 Schick B, Urbschat S. New aspects of pathogenesis of juvenile angiofibroma. Hosp Med 2004; 65: 269–273.
- 31 Amir AL, Barua M, McKnight NC, Cheng S, Yuan X, Balk SP. A direct beta-catenin-independent interaction between androgen receptor and T cell factor 4. J Biol Chem 2003; 278: 30828–30834.
- 32 Shikani AH, Richtsmeier WJ. Juvenile nasopharyngeal angiofibroma tumor models. Failure of androgens to stimulate growth in nude mice and in vitro. Arch Otolaryngol Head Neck Surg 1992; 118: 256–259.
- 33 Thornton MJ. Oestrogen functions in skin and skin appendages. Expert Opin Ther Targets 2005; 9: 617–629.
- 34 Stevenson S, Thornton J. Effects of estrogens on skin aging and the potential role of SERMs. Clin Interv Aging 2007; 2: 283–297.
- 35 Schlauder SM, Knapp C, Steffensen TS, Bui MM. Aromatase may play a critical role in the pathogenesis of juvenile nasopharyngeal angiofibroma. Fetal Pediatr Pathol 2009; 28: 232–238.
- 36 Han SW, Lei ZM, Rao CV. Treatment of human endometrial stromal cells with chorionic gonadotropin promotes their morphological and functional differentiation into decidua. Mol Cell Endocrinol 1999; 147: 7–16.
- 37 Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002; 57 Suppl 2: 2–14.
- 38 Rao CV. Physiological and pathological relevance of human uterine LH/hCG receptors. J Soc Gynecol Investig 2006; 13: 77–78.
- 39 Schick B, Kind M, Draf W, Weber R, Lackmann GM. Extranasopharyngeal angiofibroma in a 15-month-old child. Int J Pediatr Otorhinolaryngol 1998; 43: 99–104.
- 40 Riggs S, Orlandi RR. Juvenile nasopharyngeal angiofibroma recurrence associated with exogenous testosterone therapy. Head Neck 2010; 32: 812–815.
- 41 Thakar A, Gupta G, Bhalla AS, et al. Adjuvant therapy with flutamide for presurgical volume reduction in juvenile nasopharyngeal angiofibroma. Head Neck 2011; 33: 1747–1753.
- 42 Kűttner K, Katenkamp D, Stiller D. [Hormone therapy of the juvenile angiofibroma (author's transl)]. [Article in German] Arch Otorhinolaryngol 1977; 214: 331–338.
- 43 Doyle PJ, Riding K, Kahn K. Management of nasopharyngeal angiofibroma. J Otolaryngol 1977; 6: 224–232.
- 44 Johnsen S, Kloster JH, Schiff M. The action of hormones on juvenile nasopharyngeal angiofibroma. A case report. Acta Otolaryngol 1966; 61: 153–160.
- 45 Gates GA, Rice DH, Koopmann CF Jr, Schuller DE. Flutamide-induced regression of angiofibroma. Laryngoscope 1992; 102: 641–644.
- 46 Labra A, Chavolla–Magaña R, Lopez–Ugalde A, Alanis–Calderon J, Huerta–Delgado A. Flutamide as a preoperative treatment in juvenile angiofibroma (JA) with intracranial invasion: report of 7 cases. Otolaryngol Head Neck Surg 2004; 130: 466–469.
- 47 Osborne CK, Zhao H, Fuqua SA. Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 2000; 18: 3172–3186.
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