Summary
Local formation of estradiol in human breast tumors could provide a more important source of estrogen than is delivered from plasma. Prior studies have suggested that estrone is primarily synthesized from estrone sulfate. The enzyme 17β-hydroxysteroid dehydrogenase (HSD) would be required to convert estrone to estradiol.
This study characterized HSD in 1000 × g supernatants from human breast tumors. Estradiol synthesis was linearly related to tissue concentration or time over the range studied. Cofactor requirements varied with estrone concentration. High and low affinity sites were found in 50% of tissues studied, while the remainder contained only low affinity sites. Screen assays showed measurable activity in all 42 samples tested. This activity ranged from 0.73−>100 nmol estrone synthesized/g protein/hr, with a median activity of 5.9 nmol/g/hr.
We evaluated the biological relevance of the sulfatase-HSD pathway by testing the ability of estrone sulfate to stimulate colony formation in soft agar cultures of nitrosomethylurea-induced rat mammary tumors. The maximally effective concentration ranged from 10−7 to 10−4 M. Significant stimulation of colony formation was observed in 7 of 8 experiments. The estrone sulfate stimulation pattern was similar to that previously observed with estradiol. Of the3H-estrone sulfate added to the dishes, 20–98% was recovered as estrone and 0.2–6% as estradiol. These studies suggest that the requisite enzymes are present in human breast tumors for conversion of estrone sulfate to estradiol, and that this pathway may be biologically significant.
References
Stoll BA: Perspectives on hormonal therapy in cancer. In: Furr BJA (ed): Clinics in Oncology. WB Saunders, London, 1982, Vol 1, pp 3–19
Segaloff A: Hormones and mammary carcinogenesis. In: McGuire WL (ed): Breast Cancer 2: Advances in Research and Treatment, Experimental Biology. Plenum, New York, 1978, pp 1–22
Kirschner MA: The role of hormones in the development of human breast cancer. In: McGuire WL (ed): Breast Cancer 3: Advances in Research and Treatment, Current Topics. Plenum, New York, 1979, pp 199–226
Manni A, Pearson OH: Antiestrogens in tumor therapy. In: Furr BJA (ed): Clinics in Oncology. WB Saunders, London, 1982, vol 1, pp 65–75
MacDonald PC, Rombaut RP, Siiteri PK: Plasma precursors of estrogen. I. Extent of conversion of plasma Δ4-androstenedione to estrone in normal males and nonpregnant normal, castrate and adrenalectomized females. J Clin Endocrinol Metab 27: 1103–1111, 1967
Longcope C, Kato T, Horton R: Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest 48: 2191–2201, 1969
Adams JB, Li K: Biosynthesis of 17β-oestradiol in human breast carcinoma tissue and a novel method for its characterization. Brit J Cancer 31: 429–433, 1975
Abul-Hajj YJ, Iverson R, Kiang DT: Aromatization of androgens by human breast cancer. Steroids 33: 205–222, 1979
Perel E, Wilkins D, Killinger DW: The conversion of androstenedione to estrone, estradiol and testosterone in breast tissue. J Steroid Biochem 13: 89–94, 1980
Tilson-Mallett N, Santner SJ, Feil PD, Santen RJ: Biological significance of aromatase activity in human breast tumors. J Clin Endocrinol Metab 57: 1125–1128, 1983
Santner SJ, Feil PD, Santen RJ:In situ estrogen production via the estrone sulfatase pathway in breast tumors: relative importance versus the aromatase pathway. J Clin Endocrinol Metab 59: 29–33, 1984
Samojlik E, Veldhuis JD, Wells SA, Santen RJ: Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. J Clin Invest 65: 602–612, 1980
Samojlik E, Santen RJ, Worgul TJ: Plasma estrone sulfate: assessment of reduced estrogen production during treatment of metastatic breast carcinoma. Steroids 39: 497–507, 1982
Gullino PM, Pettigrew HM, Grantham FH: N-nitrosomethylurea as mammary gland carcinogen in rats. J Natl Cancer Inst 54: 401–409, 1975
Manni A, Wright C: Effect of tamoxifen and α-difluoromethylornithine on clones of nitrosomethylurea-induced rat mammary tumor cells grown in soft agar culture. Cancer Res 43: 1084–1086, 1983
Manni A, Wright C: Polyamines as mediators of estrogen action on the growth of experimental breast cancer in rats. J Natl Cancer Inst 73: 511–514, 1984
Arafah BM, Finegan HM, Roe J, Manni A, Pearson OH: Hormone dependency in N-nitrosomethylurea-induced rat mammary tumors. Endocrinology 111: 584–588, 1982
Rose DP, Noonan JJ: Influence of prolactin and growth hormone on rat mammary tumors induced by N-nitrosomethylurea. Cancer Res 42: 35–38, 1982
Hamburger A, Salmon SE: Primary bioassay of human myeloma stem cells. J Clin Invest 60: 846–854, 1977
McGuire WL, De La Garza M, Chamness GC: Evaluation of estrogen receptor assays in human breast cancer tissue. Cancer Res 37: 637–639, 1977
Feil PD, Klase JC, Margets MJ: Use of medroxyprogesterone acetate to measure cytosol progestin receptors in human breast cancer. 61st Ann Mtg of the Endocrine Society, Anaheim, CA, p 150 (Abst), 1979
Dowd JE, Riggs DS: A comparison of estimates of Michaelis-Menten kinetic constants from various linear transformations. J Biol Chem 240: 863–869, 1965
Millington DS: Determination of hormonal steroid concentrations in biological extracts by high resolution mass fragmentography. J Steroid Biochem 6: 239–245, 1975
Fishman J, Nisselbaum JS, Menendez-Botet CJ, Schwartz MK: Estrone and estradiol content in human breast tumors: relationship to estradiol receptors. J Steroid Biochem 8: 893–896, 1977
Edery M, Goussard J, Dehennin L, Scholler R, Reiffsteck J, Drosdowsky MA: Endogenous oestradiol-17β concentration in breast tumors determined by mass fragmentography and by radioimmunoassay: relationship to receptor content. Eur J Cancer 17: 115–120, 1981
Vignon F, Terqui M, Westley B, Derocq D, Rochefort H: Effects of plasma estrogen sulfates in mammary cancer cells. Endocrinology 106: 1079–1086, 1980
Brooks SC, Horn L: Hepatic sulfation of estrogen metabolites. Biochem Biophys Acta 231: 233–241, 1971
Pack BA, Tovar R, Booth E, Brooks SC: The cyclic relationship of estrogen sulfurylation to the nuclear receptor level in human endometrial curettings. J Clin Endocrinol Metab 48: 420–424, 1979
Verheugen C, Pardridge WM, Judd HL, Chaudhuri G: Differential permeability of uterine and liver vascular beds to estrogens and estrogen conjugates. J Clin Endocrinol Metab 59: 1128–1132, 1984
Santen RJ, Worgul TJ, Samojlik E, Interrante A, Boucher A, Lipton A, Harvey HA, White DS, Smart E, Cox C, Wells SA: A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med 305: 545–551, 1981
Larsen PR: Feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 306: 23–32, 1982
Bellino FL, Osawa Y: Evidence of the direct aromatization of testosterone and different aromatization sites for testosterone and androstenedione in human placental microsomes. Biochemistry 13: 1925–1931, 1974
Santner SJ, Rosen H, Osawa Y, Santen RJ: Additive effects of aminoglutethimide, testololactone, and 4-hydroxyandrostendione as inhibitors of aromatase. J Steroid Biochem 20: 1239–1242, 1984
Beranek PA, Folkerd EJ, Ghilchik MW, James VHT: 17β-Hydroxysteroid dehydrogenase and aromatase activity in breast fat from women with benign and malignant breast tumors. Clin Endocrinol 20: 205–212, 1984
Marovitz W, Loucopoulos A, Satyaswaroop PG, Gurpide E, Todd R, Naftolin F: Apparent immunologic nonidentity of human placental and endometrial 17β-estradiol dehydrogenase. Am J Obster Gynecol 138: 643–647, 1980
Pollow K, Lubbert H, Boquoi E, Kreutzer G, Jeske R, Pollow B: Studies on 17β-hydroxysteroid dehydrogenase in human endometrium and endometrial carcinoma. I. Subcellular distribution and variation of specific enzyme activity. Acta Endocrinol (Copenh) 79: 134–145, 1975
Thomas CMG, Veerkamp JH: The subcellular distribution of the 17β-hydroxysteroid dehydrogenase in the human placenta. Acta Endocrinol (Copenh) 82: 150–162, 1976
Tseng L, Gurpide E: Nuclear concentration of estradiol in superfused slices of human endometrium. Am J Obstet Gynecol 114: 995–1001, 1972
Ruh TS, Katzenellenbogen BS, Katzenellenbogen JA, Gorski J: Estrone interaction with the rat uterus:In vitro response and nuclear uptake. Endocrinology 92: 125–135, 1973
Lippman M, Monaco ME, Bolan G: Effects of estrone, estradiol, and estriol on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 37: 1901–1907, 1977
Author information
Authors and Affiliations
Additional information
This work presented in part at the International Congress on Endocrinology of the Breast, September 19–22, 1984, Torino, Italy.
Rights and permissions
About this article
Cite this article
Santner, S.J., Leszczynski, D., Wright, C. et al. Estrone sulfate: A potential source of estradiol in human breast cancer tissues. Breast Cancer Res Tr 7, 35–44 (1986). https://doi.org/10.1007/BF01886734
Issue Date:
DOI: https://doi.org/10.1007/BF01886734