Endocrinology, Vol 137, 3061-3068, Copyright © 1996 by Endocrine Society

ARTICLES

Expression of aromatase protein and messenger ribonucleic acid in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers

Q Lu, J Nakmura, A Savinov, W Yue, J Weisz, DJ Dabbs, G Wolz and A Brodie
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland 21201.

The expression of aromatase by breast cancer cells and the role of locally produced estrogen in the stimulation of tumor growth has been controversial. The present study was performed to determine the site of aromatization in human breast cancers, using both immunocytochemistry and in situ hybridization. The functional significance of locally produced estrogens on growth of the tumor was addressed by measuring aromatase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether testosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detected by ISH was also located in tumor epithelial cells and stromal cell, and the pattern of expression was the same as with immunocytochemistry. In the ten tumors that showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 +/- 18.6 (SE) fmol estrogen/mg protein.h, whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein-h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score were significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [3H]-thymidine into DNA. In two of these tumors, aromatase activity was high and [3H]- thymidine incorporation into DNA was also stimulated by testosterone. In the other two tumors that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is concluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors.

This article has been cited by other articles:

				I. Kijima, J. Ye, C. Glackin, and S. Chen CCAAT/Enhancer Binding Protein {delta} Up-regulates Aromatase Promoters I.3/II in Breast Cancer Epithelial Cells Cancer Res., June 1, 2008; 68(11): 4455 - 4464. [Abstract] [Full Text] [PDF]

				M. Rahman, S. F. Lax, C. H. Sutter, Q. T. Tran, G. L. Stevens, G. L. Emmert, J. Russo, R. J. Santen, and T. R. Sutter CYP1B1 Is Not a Major Determinant of the Disposition of Aromatase Inhibitors in Epithelial Cells of Invasive Ductal Carcinoma Drug Metab. Dispos., May 1, 2008; 36(5): 963 - 970. [Abstract] [Full Text] [PDF]

				L. F. Macedo, G. J. Sabnis, O. G. Goloubeva, and A. Brodie Combination of Anastrozole with Fulvestrant in the Intratumoral Aromatase Xenograft Model Cancer Res., May 1, 2008; 68(9): 3516 - 3522. [Abstract] [Full Text] [PDF]

				R. Rajhans, H. B. Nair, S. S. Nair, V. Cortez, K. Ikuko, N. B. Kirma, D. Zhou, A. E. Holden, D. W Brann, S. Chen, et al. Modulation of in Situ Estrogen Synthesis by Proline-, Glutamic Acid-, and Leucine-Rich Protein-1: Potential Estrogen Receptor Autocrine Signaling Loop in Breast Cancer Cells Mol. Endocrinol., March 1, 2008; 22(3): 649 - 664. [Abstract] [Full Text] [PDF]

				Y. Miki, T. Suzuki, C. Tazawa, Y. Yamaguchi, K. Kitada, S. Honma, T. Moriya, H. Hirakawa, D. B. Evans, S.-i. Hayashi, et al. Aromatase Localization in Human Breast Cancer Tissues: Possible Interactions between Intratumoral Stromal and Parenchymal Cells Cancer Res., April 15, 2007; 67(8): 3945 - 3954. [Abstract] [Full Text] [PDF]

				C. F Singer, A. Fink-Retter, D. Gschwantler-Kaulich, T. Thalhammer, G. Hudelist, R. Mueller, K. Czerwenka, and E. Kubista Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism Endocr. Relat. Cancer, December 1, 2006; 13(4): 1101 - 1107. [Abstract] [Full Text] [PDF]

				Y. HONG and S. CHEN Aromatase Inhibitors: Structural Features and Biochemical Characterization Ann. N.Y. Acad. Sci., November 1, 2006; 1089(1): 237 - 251. [Abstract] [Full Text] [PDF]

				I. Kijima, S. Phung, G. Hur, S.-L. Kwok, and S. Chen Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression Cancer Res., June 1, 2006; 66(11): 5960 - 5967. [Abstract] [Full Text] [PDF]

				O. K. Weinberg, D. C. Marquez-Garban, M. C. Fishbein, L. Goodglick, H. J. Garban, S. M. Dubinett, and R. J. Pietras Aromatase Inhibitors in Human Lung Cancer Therapy Cancer Res., December 15, 2005; 65(24): 11287 - 11291. [Abstract] [Full Text] [PDF]

				T. Suzuki, Y. Miki, Y. Nakamura, T. Moriya, K. Ito, N. Ohuchi, and H. Sasano Sex steroid-producing enzymes in human breast cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 701 - 720. [Abstract] [Full Text] [PDF]

				M. F. Bouchard, H. Taniguchi, and R. S. Viger Protein Kinase A-Dependent Synergism between GATA Factors and the Nuclear Receptor, Liver Receptor Homolog-1, Regulates Human Aromatase (CYP19) PII Promoter Activity in Breast Cancer Cells Endocrinology, November 1, 2005; 146(11): 4905 - 4916. [Abstract] [Full Text] [PDF]

				D. Jelovac, L. Macedo, O. G. Goloubeva, V. Handratta, and A. M.H. Brodie Additive Antitumor Effect of Aromatase Inhibitor Letrozole and Antiestrogen Fulvestrant in a Postmenopausal Breast Cancer Model Cancer Res., June 15, 2005; 65(12): 5439 - 5444. [Abstract] [Full Text] [PDF]

				T. Itoh, K. Karlsberg, I. Kijima, Y.-C. Yuan, D. Smith, J. Ye, and S. Chen Letrozole-, Anastrozole-, and Tamoxifen-Responsive Genes in MCF-7aro Cells: A Microarray Approach Mol. Cancer Res., April 1, 2005; 3(4): 203 - 218. [Abstract] [Full Text] [PDF]

				A. Brodie, D. Jelovac, L. Macedo, G. Sabnis, S. Tilghman, and O. Goloubeva Therapeutic Observations in MCF-7 Aromatase Xenografts Clin. Cancer Res., January 15, 2005; 11(2): 884s - 888s. [Abstract] [Full Text] [PDF]

				Y. Miyoshi, S. J. Kim, K. Akazawa, S. Kamigaki, S. Ueda, T. Yanagisawa, T. Inoue, T. Taguchi, Y. Tamaki, and S. Noguchi Down-Regulation of Intratumoral Aromatase Messenger RNA Levels by Docetaxel in Human Breast Cancers Clin. Cancer Res., December 15, 2004; 10(24): 8163 - 8169. [Abstract] [Full Text] [PDF]

				S. Chen, M. Cho, K. Karlsberg, D. Zhou, and Y.-C. Yuan Biochemical and Biological Characterization of a Novel Anti-aromatase Coumarin Derivative J. Biol. Chem., November 12, 2004; 279(46): 48071 - 48078. [Abstract] [Full Text] [PDF]

				S. J. Ellem, J. F. Schmitt, J. S. Pedersen, M. Frydenberg, and G. P. Risbridger Local Aromatase Expression in Human Prostate Is Altered in Malignancy J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2434 - 2441. [Abstract] [Full Text] [PDF]

				B. J. Long, D. Jelovac, V. Handratta, A. Thiantanawat, N. MacPherson, J. Ragaz, O. G. Goloubeva, and A. M. Brodie Therapeutic Strategies Using the Aromatase Inhibitor Letrozole and Tamoxifen in a Breast Cancer Model J Natl Cancer Inst, March 17, 2004; 96(6): 456 - 465. [Abstract] [Full Text] [PDF]

				E. T. Eng, J. Ye, D. Williams, S. Phung, R. E. Moore, M. K. Young, U. Gruntmanis, G. Braunstein, and S. Chen Suppression of Estrogen Biosynthesis by Procyanidin Dimers in Red Wine and Grape Seeds Cancer Res., December 1, 2003; 63(23): 8516 - 8522. [Abstract] [Full Text] [PDF]

				M. G. Goodin and R. J. Rosengren Epigallocatechin Gallate Modulates CYP450 Isoforms in the Female Swiss-Webster Mouse Toxicol. Sci., December 1, 2003; 76(2): 262 - 270. [Abstract] [Full Text] [PDF]

				Y. Kinoshita and S. Chen Induction of Aromatase (CYP19) Expression in Breast Cancer Cells through a Nongenomic Action of Estrogen Receptor {alpha} Cancer Res., July 1, 2003; 63(13): 3546 - 3555. [Abstract] [Full Text] [PDF]

				B. J. Long, D. Jelovac, A. Thiantanawat, and A. M. Brodie The Effect of Second-Line Antiestrogen Therapy on Breast Tumor Growth after First-Line Treatment with the Aromatase Inhibitor Letrozole: Long-Term Studies Using the Intratumoral Aromatase Postmenopausal Breast Cancer Model Clin. Cancer Res., July 1, 2002; 8(7): 2378 - 2388. [Abstract] [Full Text] [PDF]

				S. CHEN, D. ZHOU, T. OKUBO, Y.-C. KAO, E. T. ENG, B. GRUBE, A. KWON, C. YANG, and B. YU Prevention and Treatment of Breast Cancer by Suppressing Aromatase Activity and Expression Ann. N.Y. Acad. Sci., June 1, 2002; 963(1): 229 - 238. [Abstract] [Full Text] [PDF]

				G. Davies, L.-A. Martin, N. Sacks, and M. Dowsett Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention Ann. Onc., May 1, 2002; 13(5): 669 - 678. [Abstract] [Full Text] [PDF]

				T. K. Mukherjee, H. Dinh, G. Chaudhuri, and L. Nathan Testosterone attenuates expression of vascular cell adhesion molecule-1 by conversion to estradiol by aromatase in endothelial cells: Implications in atherosclerosis PNAS, March 19, 2002; 99(6): 4055 - 4060. [Abstract] [Full Text] [PDF]

				B. J Grube, E. T. Eng, Y.-C. Kao, A. Kwon, and S. Chen White Button Mushroom Phytochemicals Inhibit Aromatase Activity and Breast Cancer Cell Proliferation J. Nutr., December 1, 2001; 131(12): 3288 - 3293. [Abstract] [Full Text] [PDF]

				T. Okubo, S. C. Mok, and S. Chen Regulation of Aromatase Expression in Human Ovarian Surface Epithelial Cells J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4889 - 4899. [Abstract] [Full Text]

				C. R. Jefcoate, J. G. Liehr, R. J. Santen, T. R. Sutter, J. D. Yager, W. Yue, S. J. Santner, R. Tekmal, L. Demers, R. Pauley, et al. Chapter 5: Tissue-Specific Synthesis and Oxidative Metabolism of Estrogens J Natl Cancer Inst Monographs, July 1, 2000; 2000(27): 95 - 112. [Abstract] [Full Text] [PDF]

				J. T. Sanderson, W. Seinen, J. P. Giesy, and M. van den Berg 2-Chloro-s-Triazine Herbicides Induce Aromatase (CYP19) Activity in H295R Human Adrenocortical Carcinoma Cells: A Novel Mechanism for Estrogenicity? Toxicol. Sci., March 1, 2000; 54(1): 121 - 127. [Abstract] [Full Text] [PDF]

				R. J. Pauley, S. J. Santner, L. R. Tait, R. K. Bright, and R. J. Santen Regulated CYP19 Aromatase Transcription in Breast Stromal Fibroblasts J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 837 - 846. [Abstract] [Full Text]

				C. J. Corbin, J. M. Trant, K. W. Walters, and A. J. Conley Changes in Testosterone Metabolism Associated with the Evolution of Placental and Gonadal Isozymes of Porcine Aromatase Cytochrome P450 Endocrinology, November 1, 1999; 140(11): 5202 - 5210. [Abstract] [Full Text]

				J. Nakamura, Q. Lu, G. Aberdeen, E. Albrecht, and A. Brodie The Effect of Estrogen on Aromatase and Vascular Endothelial Growth Factor Messenger Ribonucleic Acid in the Normal Nonhuman Primate Mammary Gland J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1432 - 1437. [Abstract] [Full Text]

				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]

				N. Harada, H. Ota, N. Yoshimura, T. Katsuyama, and Y. Takagi Localized Aberrant Expression of Cytochrome P450 Aromatase in Primary and Metastatic Malignant Tumors of Human Liver J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 697 - 702. [Abstract] [Full Text]

				M. J. Reed and A. Purohit Breast Cancer and the Role of Cytokines in Regulating Estrogen Synthesis: An Emerging Hypothesis Endocr. Rev., October 1, 1997; 18(5): 701 - 715. [Abstract] [Full Text]

				S. J. Santner, R. J. Pauley, L. Tait, J. Kaseta, and R. J. Santen Aromatase Activity and Expression in Breast Cancer and Benign Breast Tissue Stromal Cells J. Clin. Endocrinol. Metab., January 1, 1997; 82(1): 200 - 208. [Abstract] [Full Text] [PDF]