Journal of Clinical Endocrinology & Metabolism, Vol 78, 736-743, Copyright © 1994 by Endocrine Society

ARTICLES

Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture

SE Bulun, ER Simpson and RA Word
Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics-Gynecology, University of Texas Southwestern Medical Center, Dallas 75235-9051.

The conversion of C19 steroids to estrogens occurs in a number of tissues and is catalyzed by a specific form of cytochrome P450, namely aromatase cytochrome P450 (P450arom). Previously, conversion of radiolabeled androstenedione to estrone has been demonstrated in uterine leiomyomas. By use of reverse transcription followed by polymerase chain reaction amplification of total RNA together with a rat cRNA as an internal standard, we detected and quantified P450arom transcripts in total RNA isolated from 32 of the 35 leiomyoma (91%) and from 18 of the 24 adjacent myometrial (75%) tissue samples from 26 women. P450arom transcripts were not detectable in myometrial tissues from disease-free uteri (n = 8). P450arom transcript levels in leiomyomas were similar to those in adipose tissue (normalized to total RNA) and were 1.5- to 25-fold higher than those in adjacent myometrial tissues. We did not find any correlation between P450arom transcript levels and leiomyoma size, histopathology, uterine weight, or patient age. In leiomyoma smooth muscle cells in culture (n = 4) and tissue explants (n = 4), aromatase activity was stimulated by dibutyryl cAMP, and this effect was potentiated by a phorbol ester. These increases in aromatase expression were accompanied by comparable increases in the levels of translatable P450arom mRNA. Treatment with dexamethasone or platelet-derived growth factor did not stimulate aromatase expression. Consistently higher levels of aromatase activity and P450arom transcripts were found in the leiomyoma tissues than in smooth muscle cells in culture (2- to 20-fold). Reverse transcription-polymerase chain reaction analysis of untranslated 5'-termini of mRNA species in leiomyomas revealed the use of primarily promoter II (the ovarian-type promoter) for CYP19 gene transcription. Leiomyomas also contain some transcripts with untranslated exon I.4 (previously found in adipose stromal cells and skin fibroblasts). Placental-type promoter-specific 5'-ends were not present in leiomyomas. We conclude that aromatase expression in leiomyomas is regulated by the rate of CYP19 gene transcription, which is, in turn, regulated by the use of tissue- specific promoters. These findings are consistent with the hypothesis that localized estrogen biosynthesis may be of pathological significance in the promotion of leiomyoma growth.

This article has been cited by other articles:

				H. Ishikawa, V. Fencki, E. E. Marsh, P. Yin, D. Chen, Y.-H. Cheng, S. Reisterd, Z. Lin, and S. E. Bulun CCAAT/Enhancer Binding Protein {beta} Regulates Aromatase Expression via Multiple and Novel Cis-Regulatory Sequences in Uterine Leiomyoma J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 981 - 991. [Abstract] [Full Text] [PDF]

				O. Bukulmez, D. B. Hardy, B. R. Carr, R. A. Word, and C. R. Mendelson Inflammatory Status Influences Aromatase and Steroid Receptor Expression in Endometriosis Endocrinology, March 1, 2008; 149(3): 1190 - 1204. [Abstract] [Full Text] [PDF]

				L. Pal, A. L. Niklaus, M. Kim, S. Pollack, and N. Santoro Heterogeneity in endometrial expression of aromatase in polyp-bearing uteri Hum. Reprod., January 1, 2008; 23(1): 80 - 84. [Abstract] [Full Text] [PDF]

				A. G. Imir, Z. Lin, P. Yin, S. Deb, B. Yilmaz, M. Cetin, A. Cetin, and S. E. Bulun Aromatase Expression in Uterine Leiomyomata Is Regulated Primarily by Proximal Promoters I.3/II J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1979 - 1982. [Abstract] [Full Text] [PDF]

				I. Velasco, J. Rueda, and P. Acien Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis Mol. Hum. Reprod., June 1, 2006; 12(6): 377 - 381. [Abstract] [Full Text] [PDF]

				E. A. Stewart and C. C. Morton The genetics of uterine leiomyomata: what clinicians need to know. Obstet. Gynecol., April 1, 2006; 107(4): 917 - 921. [Abstract] [Full Text] [PDF]

				S. E. Bulun, Z. Lin, G. Imir, S. Amin, M. Demura, B. Yilmaz, R. Martin, H. Utsunomiya, S. Thung, B. Gurates, et al. Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment Pharmacol. Rev., September 1, 2005; 57(3): 359 - 383. [Abstract] [Full Text] [PDF]

				T. Kasai, M. Shozu, K. Murakami, T. Segawa, K. Shinohara, K. Nomura, and M. Inoue Increased Expression of Type I 17{beta}-Hydroxysteroid Dehydrogenase Enhances in Situ Production of Estradiol in Uterine Leiomyoma J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5661 - 5668. [Abstract] [Full Text] [PDF]

				J. A. Rivera, S. Christopoulos, D. Small, and M. Trifiro Hormonal Manipulation of Benign Metastasizing Leiomyomas: Report of Two Cases and Review of the Literature J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3183 - 3188. [Abstract] [Full Text] [PDF]

				A. Sierra-Ramirez, T. Morato, R. Campos, I. Rubio, C. Calzada, E. Mendez, and G. Ceballos Acute effects of testosterone on intracellular Ca2+ kinetics in rat coronary endothelial cells are exerted via aromatization to estrogens Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H63 - H71. [Abstract] [Full Text] [PDF]

				T. Maruo, N. Ohara, J. Wang, and H. Matsuo Sex steroidal regulation of uterine leiomyoma growth and apoptosis Hum. Reprod. Update, May 1, 2004; 10(3): 207 - 220. [Abstract] [Full Text] [PDF]

				M. Shozu, H. Sumitani, T. Segawa, H.-J. Yang, K. Murakami, T. Kasai, and M. Inoue Overexpression of Aromatase P450 in Leiomyoma Tissue Is Driven Primarily through Promoter I.4 of the Aromatase P450 Gene (CYP19) J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2540 - 2548. [Abstract] [Full Text] [PDF]

				S. E. BULUN, S. YANG, Z. FANG, B. GURATES, M. TAMURA, and S. SEBASTIAN Estrogen Production and Metabolism in Endometriosis Ann. N.Y. Acad. Sci., March 1, 2002; 955(1): 75 - 85. [Abstract] [Full Text] [PDF]

				S. Palomba, T. Sena, R. Noia, C. Di Carlo, F. Zullo, and P. Mastrantonio Transdermal Hormone Replacement Therapy in Postmenopausal Women With Uterine Leiomyomas Obstet. Gynecol., December 1, 2001; 98(6): 1053 - 1058. [Abstract] [Full Text] [PDF]

				M. Shozu, H. Sumitani, T. Segawa, H.-J. Yang, K. Murakami, and M. Inoue Inhibition of in Situ Expression of Aromatase P450 in Leiomyoma of the Uterus by Leuprorelin Acetate J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5405 - 5411. [Abstract] [Full Text] [PDF]

				H. Sumitani, M. Shozu, T. Segawa, K. Murakami, H.-J. Yang, K. Shimada, and M. Inoue In Situ Estrogen Synthesized by Aromatase P450 in Uterine Leiomyoma Cells Promotes Cell Growth Probably Via an Autocrine/Intracrine Mechanism Endocrinology, October 1, 2000; 141(10): 3852 - 3861. [Abstract] [Full Text] [PDF]

				H. Sasano and N. Harada Intratumoral Aromatase in Human Breast, Endometrial, and Ovarian Malignancies Endocr. Rev., October 1, 1998; 19(5): 593 - 607. [Abstract] [Full Text]

				L. Dalla Valle, A. Ramina, S. Vianello, A. Fassina, P. Belvedere, and L. Colombo Potential for Estrogen Synthesis and Action in Human Normal and Neoplastic Thyroid Tissues J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3702 - 3709. [Abstract] [Full Text]

				V. R. Agarwal, K. Takayama, J. J. Van Wyk, H. Sasano, E. R. Simpson, and S. E. Bulun Molecular Basis of Severe Gynecomastia Associated with Aromatase Expression in a Fibrolamellar Hepatocellular Carcinoma J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1797 - 1800. [Abstract] [Full Text]

				M. Shozu, Y. Zhao, S. E. Bulun, and E. R. Simpson Multiple Splicing Events Involved in Regulation of Human Aromatase Expression by a Novel Promoter, I.6 Endocrinology, April 1, 1998; 139(4): 1610 - 1617. [Abstract] [Full Text] [PDF]

				L. S. Noble, K. Takayama, K. M. Zeitoun, J. M. Putman, D. A. Johns, M. M. Hinshelwood, V. R. Agarwal, Y. Zhao, B. R. Carr, and S. E. Bulun Prostaglandin E2 Stimulates Aromatase Expression in Endometriosis-Derived Stromal Cells J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 600 - 606. [Abstract] [Full Text] [PDF]