Abstract
Enzymes modulating local steroid availability play an important role in the progression of human breast cancer. These include isoforms of 17β-hydroxysteroid dehydrogenase (17-HSD), aromatase and steroid sulphatase (STS). The aim of this study was to investigate the expression, by reverse transcription polymerase chain reaction, of 17-HSD types I–IV, aromatase and steroid STS in a series of 51 human breast tumour biopsies and 22 primary cultures of epithelial and stromal cells derived from these tumours, giving a profile of the steroid-regulating network for individual tumours. Correlations between enzyme expression profiles and expression of the interleukin (IL)-6 gene were also sought. All except one tumour expressed at least one isoform of 17-HSD, either alone or in combination with aromatase and STS. Expression of 17-HSD isoforms I–IV were observed in nine tumours. Of the 15 tumours which expressed three isoforms, a combination of 17-HSD II, III and IV was most common (6/15 samples). The majority of tumours (n = 17) expressed two isoforms of 17-HSD with combinations of 17-HSD II and IV predominant (7/17 samples). Eight tumours expressed a single isoform and of these, 17-HSD I was in the majority (5/8 samples). In primary epithelial cultures, enzyme expression was ranked: HSD I (86%) > STS (77%) > HSD II (59%) > HSD IV (50%) = aromatase (50%) > HSD III (32%). Incidence of enzyme expression was generally reduced in stromal cultures which were ranked: HSD I (68%) > STS (67%) > aromatase (48%) > HSD II (43%) > HSD IV (28%) > HSD III (19%). Expression of IL-6 was associated with tumours that expressed ≥ 3 steroid-converting enzymes. These tumours were of higher grade and tended to come from patients with family history of breast cancer. In conclusion, we propose that these enzymes work in tandem with cytokines thereby providing sufficient quantities of bioactive oestrogen from less active precursors which stimulates tumour growth.
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16 November 2011
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References
Adams, EF, Rafferty, B & White, MC (1991) Interleukin 6 is secreted by breast fibroblasts and stimulates 17β-oestradiol oxidoreductase activity in MCF-7 cells: possible paracrine regulation of 17β-oestradiol levels. Int J Cancer 49: 118–121
Adamski, J, Normand, T, Leenders, F, Monte, D, Begue, A, Stehelin, D, Jungblut, PW & de Launoit, Y (1992) Molecular cloning of a novel widely expressed human 80 kDa 17β-hydroxysteroid dehydrogenase IV. Biochem J 311: 437–443
Andersson, S (1995) 17β-hydroxysteroid dehydrogenase: isozymes and mutations. J Endocrinol 146: 197–200
Boyle-Walsh, E, Birch, MA, Gallagher, J, Speirs, V, White, MC, Shenkin, A & Fraser, WD (1996) RT-PCR detection of cytokine transcripts in a series of cultured human meningiomas. J Pathol 178: 442–446
Casey, ML, Macdonald, PC & Andersson, S (1994) 17β-hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. J Clin Invest 94: 2135–2141
Castagnetta, LAM, Carruba, G, Traina, A, Granata, OM, Markus, M, Pavone-Macaluso, M, Blomquist, CH & Adamski, J (1997) Expression of different 17β-hydroxysteroid dehydrogenase types and their activities in human prostate cancer cells. Endocrinology 138: 4876–4882
Corbould, AM, Judd, SJ & Rodgers, RJ (1998) Expression of types 1, 2 and 3 17β-hydroxysteroid dehydrogenase in subcutaneous abdominal and intra-abdominal adipose tissue of women. J Clin Endo Metab 83: 187–194
Deyashiki, Y, Ohshima, K, Nakanishi, M, Sato, K, Matsuura, K & Hara, A (1995) Molecular cloning and characterisation of mouse estradiol 17β-dehydrogenase (A-specific), a member of the aldoketoreductase family. J Biol Chem 270: 10461–10467
Elo, JP, Akinola, LA, Poutanen, M, Vihko, P, Kyllonen, AP, Lukkarinen, O & Vihko, R (1996) Characterisation of 17β-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate. Int J Cancer 66: 37–41
English, M, Robinson, E, Hughes, SV, Morton, D, Langman, MJ, Stewart, PM & Hewison, M (1997) Demonstration in vitro and in vivo of oestrogen metabolism in colonic cancer tissue. J Endocrinol Suppl 152: P95
Green, AR, Green, VL, White, MC & Speirs, V (1997) Expression of cytokine messenger RNA in normal and neoplastic human breast tissue: identification of interleukin-8 as a potential regulatory factor in breast tumours. Int J Cancer 72: 937–941
Green, VL, Speirs, V, Jeffreys, RV, Foy, P, Landolt, AM & Atkin, SL (1999) 17β-hydroxysteroid dehydrogenase type 1, 2, 3 and 4 expression and enzyme activity in human anterior pituitary adenomas. J Clin Endo Metab 84: 1340–1345
Guengerich, FP (1992) Characterisation of human cytochrome P450 enzymes. FASEB J 6: 745–748
James, VHT, McNeill, JM, Lai, LC, Newton, CJ, Ghilchik, MW & Reed, MJ (1987) Aromatase activity in normal breast and breast tumour tissue: in vivo and in vitro studies. Steroids 50: 269–279
Jornvall, H, Person, B, Krook, M, Atrain, S, Gonzalez-Duatre, R, Jeffrey, J & Ghosh, D (1995) Short-chain dehydrogenases/reductases (SDR). Biochem 34: 6003–6013
Kurebayashi, S, Miyashita, Y, Hirose, T, Kasayama, S, Akira, S & Kishimoto, T (1997) Characterisation of mechanisms of interleukin-6 repression by estrogen receptor. J Steroid Biochem Mol Biol 60: 11–17
Labrie, F, Luu-The, V, Lin, S-X, Labrie, C, Simard, J, Breton, R & Belanger, A (1997) The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology. Steroids 62: 148–158
Lu, Q, Nakmura, J, Savinov, A, Yue, W, Weisz, J, Dabbs, DJ, Wolz, G & Brodie, A (1996) Expression of aromatase protein and messenger ribonucleic acid in tumour epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers. Endocrinology 137: 3061–3068
Luu-The, V, Zhang, Y, Poirier, D & Labrie, F (1995) Characteristics of human types 1, 2 and 3 17β-hydroxysteroid dehydrogenase activities: oxidation/reduction and inhibition. J Steroid Biochem Molec Biol 55: 581–587
Nokelainen, PA, Peltoketo, H, Vihko, RK & Vihko, PT (1998) Expression cloning of a novel mouse 17β-hydroxysteroid dehydrogenase/17-ketosteroid reductase, an enzyme of estradiol biosynthesis in the corpus luteum. Proc Am Endo Soc, P1–279
Pasqualini, JR, Chetrite, G, Blacker, C, Feinstein, MC, Delonde, L, Talbi, M & Maloche, C (1996a) Concentrations of estrone, estradiol and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and post-menopausal breast cancer patients. J Clin Endocrinol Metab 81: 1460–1464
Pasqualini, JR, Chetrite, G & Le Nestour, E (1996b) Control and expression of oestrone sulphatase activities in human breast cancer. J Endocrinol 150: S99–S105
Peltoketo, H, Isomaa, V & Vihko, R (1996) Expression and regulation of 17β-hydroxysteroid dehydrogenase type I. J Endocrinol 150: S21–S30
Penning, TM (1996) Molecular endocrinology of hydroxysteroid dehydrogenases. Endocrine Rev 18: 281–305
Purohit, A, Duncan, LJ, Wang, DY, Coldham, NG, Ghilchik, MW & Reed, MJ (1997) Paracrine control of oestrogen production in breast cancer. Endocrine Rel Cancer 4: 323–330
Ray, A, Prefontaine, KE & Ray, P (1994) Down-modulation of interleukin-6 gene by 17β-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem 269: 12940–12946
Reed, MJ & Purohit, A (1997) Breast cancer and the role of cytokines in regulating estrogen synthesis: An emerging hypothesis. Endo Rev 18: 701–705
Reed, MJ, Purohit, A, Howarth, NM & Potter, BVL (1994) Steroid sulphatase inhibitors: a new endocrine therapy. Drugs Future 19: 673–680
Santen, RJ, Martel, J, Hoahland, F, Naftolin, F, Roa, L, Harada, N, Hafer, L, Zaino, R & Santer, SJ (1994) Stromal spindle cells contain aromatase in human breast tumours. J Clin Endo Metab 79: 627–632
Santer, SJ, Feil, PD & Santen, RJ (1984) In situ estrogen production via the estrone sulphatase pathway in breast tumours: relative importance versus the aromatase pathway. J Clin Endo Metab 59: 29–33
Sasano, H, Frost, AR, Saitoh, R, Harada, N, Poutanen, M, Vihko, R, Bulun, SE, Silverberg, SG & Nagura, H (1996) Aromatase and 17β-hydroxysteroid dehydrogenase type I in human breast carcinoma. J Clin Endo Metab 81: 4042–4045
Simpson, ER, Mahendroo, MS, Means, GD, Kilgore, MW, Hinshelwood, MM, Graham-Lorence, S, Amarneh, B, Ito, Y, Fisher, CR, Michael, MD, Mendelson, CR & Bulun, SE (1994) Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endo Rev 15: 342–355
Sovak, MA, Bellas, RE, Kim, DW, Zanieski, GJ, Rogers, AE, Traish, AM & Sonenshein, GE (1997) Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest 100: 2952–2960
Speirs, V, Adams, EF, Rafferty, B & White, MC (1993) Interactive effects of interleukin-6, 17β-estradiol and progesterone on growth and 17β-hydroxysteroid dehydrogenase activity of human breast carcinoma cells. J Steroid Biochem Mol Biol 46: 11–15
Speirs, V, Green, AR & White, MC (1996a) Collagenase III: a superior enzyme for complete disaggregation and improved viability of normal and malignant human breast tissue. InVitro Cell Dev Biol 32: 72–74
Speirs, V, Green, AR & White, MC (1996b) A comparative study of cytokine gene transcripts in normal and malignant human breast tissue and primary cell cultures derived from the same tissue samples. Int J Cancer 66: 551–556
Speirs, V, Green, AR, Walton, DS, Kerin, MJ, Fox, JN, Carleton, PJ, Desai, SB & Atkin, SL (1998a) Short-term primary culture of epithelial cells derived from breast tumours. Br J Cancer 78: 1421–1429
Speirs, V, Green, AR & Atkin, SL (1998b) Expression and activity of 17β-hydroxysteroid dehydrogenase type I in primary cultures of epithelial and stromal cells derived from normal and tumourous human breast tissue: The role of IL-8. J Steroid Biochem Mol Biol 67: 267–274
Tilson-Mallet, N, Santer, SJ, Feil, PD & Santen, RJ (1983) Biological significance of aromatase activity in human breast tumours. J Clin Endo Metab 57: 1125–1128
Zhang, Y, Word, RA, Fesmire, S, Carr, BR & Rainey, WE (1996) Human ovarian expression of 17β-hydroxysteroid dehydrogenase types 1, 2 and 3. J Clin Endo Metab 81: 3594–3598
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Speirs, V., Walton, D., Hall, MC. et al. In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6. Br J Cancer 81, 690–695 (1999). https://doi.org/10.1038/sj.bjc.6690749
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DOI: https://doi.org/10.1038/sj.bjc.6690749
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