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. 2000 Nov 22;83(11):1488–1494. doi: 10.1054/bjoc.2000.1463

Progesterone receptor isoforms A and B in human epithelial ovarian carcinoma: immunohistochemical and RT-PCR studies

J Akahira 1,2, T Inoue 1, T Suzuki 1, K Ito 2, R Konno 2, S Sato 2, T Moriya 1, K Okamura 2, A Yajima 2, H Sasano 1
PMCID: PMC2363436  PMID: 11076658

Abstract

Human epithelial ovarian carcinoma is well-known as a sex steroid-dependent neoplasm, but the possible biological significance of progesterone receptor (PR) in this cancer remains controversial. Recently, two isoforms of human PR, PRA and PRB, have been characterized and different functional characteristics have been reported for these two isoforms. We therefore examined immunohistochemistry (107 cases) and reverse transcription-polymerase chain reaction (RT-PCR) (16 cases) for PRA, PRB, and oestrogen receptor-a (ER-a). Labeling indices (LI) for PRA and PRB were 2.4 and 43.6, respectively, and the difference was statistically significant. PRB LI, but not PRA LI, as well as performance status, stage, and residual tumour turned out to be independent prognostic factors following multivariate analysis. There was also a significant correlation between ER-a LI and PRB LI (r = 0.595, P < 0.0001), suggestive of a possible interaction between these two receptors. RT-PCR also detected the expression of PR isoform transcripts in the same pattern as was observed with immunohistochemistry. Results of these studies indicate that PRA and PRB both mediate distinct pathways of progesterone action in ovarian carcinoma. Moreover, it is important to examine PRB LI as a prognostic factor in the cases of human epithelial ovarian carcinoma. © 2000 Cancer Research Campaign http://www.bjcancer.com

Keywords: progesterone receptor, PRA, PRB, ovarian cancer, RT-PCR, immunohistochemistry

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Selected References

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  1. Ahlgren J. D., Ellison N. M., Gottlieb R. J., Laluna F., Lokich J. J., Sinclair P. R., Ueno W., Wampler G. L., Yeung K. Y., Alt D. Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program. J Clin Oncol. 1993 Oct;11(10):1957–1968. doi: 10.1200/JCO.1993.11.10.1957. [DOI] [PubMed] [Google Scholar]
  2. Benraad T. J., Friberg L. G., Koenders A. J., Kullander S. Do estrogen and progesterone receptors (E2R and PR) in metastasizing endometrial cancers predict the response to gestagen therapy? Acta Obstet Gynecol Scand. 1980;59(2):155–159. doi: 10.3109/00016348009154633. [DOI] [PubMed] [Google Scholar]
  3. Bizzi A., Codegoni A. M., Landoni F., Marelli G., Marsoni S., Spina A. M., Torri W., Mangioni C. Steroid receptors in epithelial ovarian carcinoma: relation to clinical parameters and survival. Cancer Res. 1988 Nov 1;48(21):6222–6226. [PubMed] [Google Scholar]
  4. Bloom N. D., Tobin E. H., Schreibman B., Degenshein G. A. The role of progesterone receptors in the management of advanced breast cancer. Cancer. 1980 Jun 15;45(12):2992–2997. doi: 10.1002/1097-0142(19800615)45:12<2992::aid-cncr2820451218>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  5. Clarke C. L., Sutherland R. L. Progestin regulation of cellular proliferation. Endocr Rev. 1990 May;11(2):266–301. doi: 10.1210/edrv-11-2-266. [DOI] [PubMed] [Google Scholar]
  6. Clarke C. L., Zaino R. J., Feil P. D., Miller J. V., Steck M. E., Ohlsson-Wilhelm B. M., Satyaswaroop P. G. Monoclonal antibodies to human progesterone receptor: characterization by biochemical and immunohistochemical techniques. Endocrinology. 1987 Sep;121(3):1123–1132. doi: 10.1210/endo-121-3-1123. [DOI] [PubMed] [Google Scholar]
  7. Critchley H. O., Wang H., Kelly R. W., Gebbie A. E., Glasier A. F. Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system. Hum Reprod. 1998 May;13(5):1210–1217. doi: 10.1093/humrep/13.5.1210. [DOI] [PubMed] [Google Scholar]
  8. Del Campo J. M., Felip E., Rubio D., Vidal R., Bermejo B., Colomer R., Zanon V. Long-term survival in advanced ovarian cancer after cytoreduction and chemotherapy treatment. Gynecol Oncol. 1994 Apr;53(1):27–32. doi: 10.1006/gyno.1994.1082. [DOI] [PubMed] [Google Scholar]
  9. Ehrlich C. E., Young P. C., Cleary R. E. Cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications. Am J Obstet Gynecol. 1981 Nov 1;141(5):539–546. doi: 10.1016/s0002-9378(15)33275-0. [DOI] [PubMed] [Google Scholar]
  10. Erhardt K., Auer G., Björkholm E., Forsslund G., Moberger B., Sifverswärd C., Wicksell G., Zetterberg A. Prognostic significance of nuclear DNA content in serous ovarian tumors. Cancer Res. 1984 May;44(5):2198–2202. [PubMed] [Google Scholar]
  11. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Friedlander M. L., Quinn M. A., Fortune D., Foo M. S., Toppila M., Hudson C. N., Russell P. The relationship of steroid receptor expression to nuclear DNA distribution and clinicopathological characteristics in epithelial ovarian tumors. Gynecol Oncol. 1989 Feb;32(2):184–190. doi: 10.1016/s0090-8258(89)80031-9. [DOI] [PubMed] [Google Scholar]
  13. Fujimoto J., Hirose R., Ichigo S., Sakaguchi H., Li Y., Tamaya T. Expression of progesterone receptor form A and B mRNAs in uterine leiomyoma. Tumour Biol. 1998;19(2):126–131. doi: 10.1159/000029983. [DOI] [PubMed] [Google Scholar]
  14. Fujimoto J., Ichigo S., Hori M., Nishigaki M., Tamaya T. Expression of progesterone receptor form A and B mRNAs in gynecologic malignant tumors. Tumour Biol. 1995;16(4):254–260. doi: 10.1159/000217942. [DOI] [PubMed] [Google Scholar]
  15. Geisler J. P., Wiemann M. C., Miller G. A., Geisler H. E. Estrogen and progesterone receptor status as prognostic indicators in patients with optimally cytoreduced stage IIIc serous cystadenocarcinoma of the ovary. Gynecol Oncol. 1996 Mar;60(3):424–427. doi: 10.1006/gyno.1996.0067. [DOI] [PubMed] [Google Scholar]
  16. Giangrande P. H., Pollio G., McDonnell D. P. Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem. 1997 Dec 26;272(52):32889–32900. doi: 10.1074/jbc.272.52.32889. [DOI] [PubMed] [Google Scholar]
  17. Graham J. D., Roman S. D., McGowan E., Sutherland R. L., Clarke C. L. Preferential stimulation of human progesterone receptor B expression by estrogen in T-47D human breast cancer cells. J Biol Chem. 1995 Dec 22;270(51):30693–30700. doi: 10.1074/jbc.270.51.30693. [DOI] [PubMed] [Google Scholar]
  18. Graham J. D., Yeates C., Balleine R. L., Harvey S. S., Milliken J. S., Bilous A. M., Clarke C. L. Progesterone receptor A and B protein expression in human breast cancer. J Steroid Biochem Mol Biol. 1996 Jan;56(1-6):93–98. doi: 10.1016/0960-0760(95)00226-x. [DOI] [PubMed] [Google Scholar]
  19. Heintz A. P., Hacker N. F., Berek J. S., Rose T. P., Munoz A. K., Lagasse L. D. Cytoreductive surgery in ovarian carcinoma: feasibility and morbidity. Obstet Gynecol. 1986 Jun;67(6):783–788. doi: 10.1097/00006250-198606000-00007. [DOI] [PubMed] [Google Scholar]
  20. Hempling R. E., Piver M. S., Eltabbakh G. H., Recio F. O. Progesterone receptor status is a significant prognostic variable of progression-free survival in advanced epithelial ovarian cancer. Am J Clin Oncol. 1998 Oct;21(5):447–451. doi: 10.1097/00000421-199810000-00005. [DOI] [PubMed] [Google Scholar]
  21. Hirasawa G., Sasano H., Takahashi K., Fukushima K., Suzuki T., Hiwatashi N., Toyota T., Krozowski Z. S., Nagura H. Colocalization of 11 beta-hydroxysteroid dehydrogenase type II and mineralocorticoid receptor in human epithelia. J Clin Endocrinol Metab. 1997 Nov;82(11):3859–3863. doi: 10.1210/jcem.82.11.4337. [DOI] [PubMed] [Google Scholar]
  22. Horwitz K. B., Alexander P. S. In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation. Endocrinology. 1983 Dec;113(6):2195–2201. doi: 10.1210/endo-113-6-2195. [DOI] [PubMed] [Google Scholar]
  23. Horwitz K. B. Is a functional estrogen receptor always required for progesterone receptor induction in breast cancer? J Steroid Biochem. 1981 Dec;15:209–217. doi: 10.1016/0022-4731(81)90277-6. [DOI] [PubMed] [Google Scholar]
  24. Iversen O. E., Skaarland E., Utaaker E. Steroid receptor content in human ovarian tumors: survival of patients with ovarian carcinoma related to steroid receptor content. Gynecol Oncol. 1986 Jan;23(1):65–76. doi: 10.1016/0090-8258(86)90117-4. [DOI] [PubMed] [Google Scholar]
  25. Jeltsch J. M., Krozowski Z., Quirin-Stricker C., Gronemeyer H., Simpson R. J., Garnier J. M., Krust A., Jacob F., Chambon P. Cloning of the chicken progesterone receptor. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5424–5428. doi: 10.1073/pnas.83.15.5424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kastner P., Krust A., Turcotte B., Stropp U., Tora L., Gronemeyer H., Chambon P. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990 May;9(5):1603–1614. doi: 10.1002/j.1460-2075.1990.tb08280.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Katzenellenbogen B. S., Norman M. J. Multihormonal regulation of the progesterone receptor in MCF-7 human breast cancer cells: interrelationships among insulin/insulin-like growth factor-I, serum, and estrogen. Endocrinology. 1990 Feb;126(2):891–898. doi: 10.1210/endo-126-2-891. [DOI] [PubMed] [Google Scholar]
  28. Kauppila A. Progestin therapy of endometrial, breast and ovarian carcinoma. A review of clinical observations. Acta Obstet Gynecol Scand. 1984;63(5):441–450. doi: 10.3109/00016348409156700. [DOI] [PubMed] [Google Scholar]
  29. Kommoss F., Pfisterer J., Thome M., Schäfer W., Sauerbrei W., Pfleiderer A. Steroid receptors in ovarian carcinoma: immunohistochemical determination may lead to new aspects. Gynecol Oncol. 1992 Dec;47(3):317–322. doi: 10.1016/0090-8258(92)90133-4. [DOI] [PubMed] [Google Scholar]
  30. Kraus W. L., Weis K. E., Katzenellenbogen B. S. Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors. Mol Cell Biol. 1995 Apr;15(4):1847–1857. doi: 10.1128/mcb.15.4.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kumar N. S., Richer J., Owen G., Litman E., Horwitz K. B., Leslie K. K. Selective down-regulation of progesterone receptor isoform B in poorly differentiated human endometrial cancer cells: implications for unopposed estrogen action. Cancer Res. 1998 May 1;58(9):1860–1865. [PubMed] [Google Scholar]
  32. Langdon S. P., Gabra H., Bartlett J. M., Rabiaz G. J., Hawkins R. A., Tesdale A. L., Ritchie A. A., Miller W. R., Smyth J. F. Functionality of the progesterone receptor in ovarian cancer and its regulation by estrogen. Clin Cancer Res. 1998 Sep;4(9):2245–2251. [PubMed] [Google Scholar]
  33. Mangal R. K., Wiehle R. D., Poindexter A. N., 3rd, Weigel N. L. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol. 1997 Nov-Dec;63(4-6):195–202. doi: 10.1016/s0960-0760(97)00119-2. [DOI] [PubMed] [Google Scholar]
  34. Masood S., Heitmann J., Nuss R. C., Benrubi G. I. Clinical correlation of hormone receptor status in epithelial ovarian cancer. Gynecol Oncol. 1989 Jul;34(1):57–60. doi: 10.1016/0090-8258(89)90107-8. [DOI] [PubMed] [Google Scholar]
  35. McGuire W. L. Steroid receptors in human breast cancer. Cancer Res. 1978 Nov;38(11 Pt 2):4289–4291. [PubMed] [Google Scholar]
  36. Mote P. A., Balleine R. L., McGowan E. M., Clarke C. L. Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. J Clin Endocrinol Metab. 1999 Aug;84(8):2963–2971. doi: 10.1210/jcem.84.8.5928. [DOI] [PubMed] [Google Scholar]
  37. Nakashima N., Nagasaka T., Fukata S., Oiwa N., Nara Y., Fukatsu T., Takeuchi J. Study of ovarian tumors treated at Nagoya University Hospital, 1965-1988. Gynecol Oncol. 1990 Apr;37(1):103–111. doi: 10.1016/0090-8258(90)90317-e. [DOI] [PubMed] [Google Scholar]
  38. Omura G. A., Brady M. F., Homesley H. D., Yordan E., Major F. J., Buchsbaum H. J., Park R. C. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol. 1991 Jul;9(7):1138–1150. doi: 10.1200/JCO.1991.9.7.1138. [DOI] [PubMed] [Google Scholar]
  39. Osborne C. K., Yochmowitz M. G., Knight W. A., 3rd, McGuire W. L. The value of estrogen and progesterone receptors in the treatment of breast cancer. Cancer. 1980 Dec 15;46(12 Suppl):2884–2888. doi: 10.1002/1097-0142(19801215)46:12+<2884::aid-cncr2820461429>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  40. Piver M. S., Lele S. B., Marchetti D. L., Baker T. R., Tsukada Y., Emrich L. J. The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma. J Clin Oncol. 1988 Jun;6(6):983–989. doi: 10.1200/JCO.1988.6.6.983. [DOI] [PubMed] [Google Scholar]
  41. Rao B. R., Slotman B. J. Endocrine factors in common epithelial ovarian cancer. Endocr Rev. 1991 Feb;12(1):14–26. doi: 10.1210/edrv-12-1-14. [DOI] [PubMed] [Google Scholar]
  42. Redman J. R., Petroni G. R., Saigo P. E., Geller N. L., Hakes T. B. Prognostic factors in advanced ovarian carcinoma. J Clin Oncol. 1986 Apr;4(4):515–523. doi: 10.1200/JCO.1986.4.4.515. [DOI] [PubMed] [Google Scholar]
  43. Sasano H., Frost A. R., Saitoh R., Harada N., Poutanen M., Vihko R., Bulun S. E., Silverberg S. G., Nagura H. Aromatase and 17 beta-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endocrinol Metab. 1996 Nov;81(11):4042–4046. doi: 10.1210/jcem.81.11.8923858. [DOI] [PubMed] [Google Scholar]
  44. Savouret J. F., Misrahi M., Milgrom E. Molecular action of progesterone. Int J Biochem. 1990;22(6):579–594. doi: 10.1016/0020-711x(90)90033-y. [DOI] [PubMed] [Google Scholar]
  45. Sevelda P., Denison U., Schemper M., Spona J., Vavra N., Salzer H. Oestrogen and progesterone receptor content as a prognostic factor in advanced epithelial ovarian carcinoma. Br J Obstet Gynaecol. 1990 Aug;97(8):706–712. doi: 10.1111/j.1471-0528.1990.tb16243.x. [DOI] [PubMed] [Google Scholar]
  46. Shughrue P. J., Lubahn D. B., Negro-Vilar A., Korach K. S., Merchenthaler I. Responses in the brain of estrogen receptor alpha-disrupted mice. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11008–11012. doi: 10.1073/pnas.94.20.11008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Simpson B. J., Langdon S. P., Rabiasz G. J., Macleod K. G., Hirst G. L., Bartlett J. M., Crew A. J., Hawkins R. A., Macineira-Perez P. P., Smyth J. F. Estrogen regulation of transforming growth factor-alpha in ovarian cancer. J Steroid Biochem Mol Biol. 1998 Feb;64(3-4):137–145. doi: 10.1016/s0960-0760(97)00159-3. [DOI] [PubMed] [Google Scholar]
  48. Slotman B. J., Kühnel R., Rao B. R., Dijkhuizen G. H., de Graaff J., Stolk J. G. Importance of steroid receptors and aromatase activity in the prognosis of ovarian cancer: high tumor progesterone receptor levels correlate with longer survival. Gynecol Oncol. 1989 Apr;33(1):76–81. doi: 10.1016/0090-8258(89)90607-0. [DOI] [PubMed] [Google Scholar]
  49. Syvälä H., Vienonen A., Ylikomi T., Bläuer M., Zhuang Y. H., Tuohimaa P. Expression of the chicken progesterone receptor forms A and B is differentially regulated by estrogen in vivo. Biochem Biophys Res Commun. 1997 Feb 24;231(3):573–576. doi: 10.1006/bbrc.1997.6149. [DOI] [PubMed] [Google Scholar]
  50. Vegeto E., Shahbaz M. M., Wen D. X., Goldman M. E., O'Malley B. W., McDonnell D. P. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol. 1993 Oct;7(10):1244–1255. doi: 10.1210/mend.7.10.8264658. [DOI] [PubMed] [Google Scholar]
  51. Viville B., Charnock-Jones D. S., Sharkey A. M., Wetzka B., Smith S. K. Distribution of the A and B forms of the progesterone receptor messenger ribonucleic acid and protein in uterine leiomyomata and adjacent myometrium. Hum Reprod. 1997 Apr;12(4):815–822. doi: 10.1093/humrep/12.4.815. [DOI] [PubMed] [Google Scholar]
  52. Volm M., Brüggemann A., Günther M., Kleine W., Pfleiderer A., Vogt-Schaden M. Prognostic relevance of ploidy, proliferation, and resistance-predictive tests in ovarian carcinoma. Cancer Res. 1985 Oct;45(10):5180–5185. [PubMed] [Google Scholar]
  53. Wang H., Critchley H. O., Kelly R. W., Shen D., Baird D. T. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod. 1998 Apr;4(4):407–412. doi: 10.1093/molehr/4.4.407. [DOI] [PubMed] [Google Scholar]
  54. Wen D. X., Xu Y. F., Mais D. E., Goldman M. E., McDonnell D. P. The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells. Mol Cell Biol. 1994 Dec;14(12):8356–8364. doi: 10.1128/mcb.14.12.8356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Young R. C., Chabner B. A., Hubbard S. P., Fisher R. I., Bender R. A., Anderson T., Simon R. M., Canellos G. P., DeVita V. T., Jr Advanced ovarian adenocarcinoma. A prospective clinical trial of melphalan (L-PAM) versus combination chemotherapy. N Engl J Med. 1978 Dec 7;299(23):1261–1266. doi: 10.1056/NEJM197812072992301. [DOI] [PubMed] [Google Scholar]

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