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Significance of Aromatase Activity in Human Breast Cancer1

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Significance of Aromatase Activity in Human Breast Cancer1 [CANCER RESEARCH (SUPPL.) 42. 3365s-3368s. August 1982] 0008-5472/82/0042-OOOOS02.00 Significance of Aromatase Activity in Human Breast Cancer1 W. R. Miller, R. A. Hawkins, and A. P. M. Forrest University Department of Clinical Surgery, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland Abstract 3H]testosterone (8.9 Ci/mmol). The reaction was stopped by the ad dition of methanol, and 500 ¿igofnonradioactive estradiol were added The significance of in vitro aromatization of [7a-3H]testoster- to monitor losses during purification and characterization. Estradiol one to estradici by human breast cancer has been investigated was extracted and purified by thin-layer chromatography (14, 15). by correlation with (a) estrogen receptor activity and (b) clinical Characterization was by chemical derivative formation (14) and was response to endocrine therapy. Evidence for estradiol synthe based on Chromatographie behavior of parent and derivatized estradiol sis was obtained in 66 and estrogen receptor activity in 81 of being identical with that of authentic steroids and by the maintenance 110 tumors. Whereas most estrogen receptor-positive tumors of consistent specific radioactivity throughout the procedures. Synthe synthesized estradiol, the majority of receptor-negative tumors sis was determined by measuring radioactivity in the purified estradiol fraction. Conversions in excess of 0.02% of the original precursor are did not. This tendency for aromatization to be associated with estrogen receptor-positive tumors was statistically significant detectable. Estrogen Receptors. Concentration of estrogen receptor was de (p < 0.005). Mean level of receptor was also significantly termined by saturation analysis (5). Tumor cytosol was incubated higher in tumors with aromatization than in tumors without overnight at 4°with 17/?-[2,4,6,7-3H]estradiol and varying amounts of estradiol synthesis (p < 0.001 ). Forty patients with advanced nonradioactive 17/î-estradiol. Separation of free and bound steroid breast cancer have been treated by endocrine therapy. There was by addition of dextran-coated charcoal; the bound fraction was was a significant trend for tumors with aromatization to be measured by liquid scintillation counting. Concentration of receptors associated with response to treatment (p < 0.05), but the was determined by Scatchard analysis (23). Activities in excess of 5 correlation was not absolute and may simply reflect the asso fmol/mg cytosol protein were designated receptor positive (8). ciation between aromatase activity and estrogen receptors. Clinical Response. Forty patients with advanced breast cancer were Within the small subgroup of patients treated with aminoglu- treated with endocrine procedures including oophorectomy, adrenal ectomy, hypophysectomy, tamoxifen, diethylstilbestrol, and aminoglu- tethimide or adrenalectomy, tumors with high aromatase activ tethimide. ity responded whereas those without aromatization did not. For the purpose of this study, objective response to treatment was Tumor estrogen biosynthesis may therefore be of clinical sig graded independently by 2 members of the Department of Clinical nificance in selecting patients for treatments which remove Surgery who did not know the results of the biochemical studies. sources of precursor for aromatization or inhibit aromatase Patients were classified as having a response if they showed evidence activity itself. of tumor regression during therapy. Results Introduction Evidence for estradiol synthesis from testosterone was ob Many groups (4, 7, 14, 24) have now demonstrated that tained in 66 of the human breast cancers examined (60%). some breast cancers synthesize estrogen from androgen pre Level of conversion is shown in Chart 1 and ranged from 0.02 cursors in vitro. It is not known whether this potential for to 0.5%. aromatization is merely an example of tumor differentiation or Estrogen receptor activity was detected in 81 tumors (74%), whether it is of significance to the need of the tumor for and the relationship between the presence of receptors and estrogens. In the latter event, correlations between tumor aro potential for aromatization is shown in Table 1. Most estrogen matase and hormonal sensitivity would be expected. receptor-positive tumors (68%) synthesized estradiol, whereas In this study, we have related tumor aromatase activity to only the minority of receptor-negative tumors (38%) did so. estrogen receptors and, in a small group of patients with This tendency for aromatization to be associated with estrogen advanced breast cancer, to response to endocrine treatment. receptor-positive tumors was statistically significant (p < 0.005). Materials and Methods Tumors with aromatizing capacity were not only more likely to have estrogen receptor activity but, in addition, the mean Tumors. Breast cancer tissue was obtained from 110 patients. Of level of receptor of these tumors was significantly higher than these, 24 were premenopausal, 4 were menopausal (less than 5 years that in tumors lacking estradiol synthesis (Chart 2). The con since the last menstrual period), and 82 were postmenopausal. verse was not so; amounts of estrogen synthesized by tumors Tumor was obtained at mastectomy or by biopsy and immediately placed on ice. Following removal of tissue for histopathological diag with receptors did not differ significantly from those without nosis, the remainder was assayed for estrogen synthesis (aromatase receptors. In tumors with both aromatizing and estrogen recep activity) and estrogen receptor activity. tor activity, no significant quantitative relationship was found Estrogen Synthesis. A portion of each tumor (0.5 g) was finely (Chart 3). minced and incubated for 2 hr at 37°in Krebs-Ringer phosphate buffer, The relationship between tumor potential for aromatization pH 7.4, containing an NADPH-generating system and 22.5 /iCi [7a- and clinical response of 40 patients with advanced breast ' Presented at the Conference "Aromatase: New Perspectives for Breast cancer treated with endocrine therapy is presented in Chart 4. Cancer," December 6 to 9, 1981, Key Biscayne, Fla. Supported by grants from There was a statistically significant trend for aromatization to the Cancer Research Campaign and the CIBA-Geigy Corp. be associated with response, but the correlation was not ab- AUGUST 1982 3365s Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1982 American Association for Cancer Research. W. R. Miller et al. 05-1 . 820 estradiol '783 700- conversion estrogen receptor 03- tmol "mg600- cytosol protein 500- 02- ¿00- 0 1- 300- s t •¿ 200- •¿ Chart 1. Level of estradiol synthesis in tumors with aromatization. _Ä- 100- Table 1 á Correlation between potential for aromatization and presence of estrogen receptor X* = 7.99; p - 0.005. Estrogen syn- Without syn estradiol synthesis no synthesis thesis thesis Chart 2. Level of estrogen receptor in tumors with and without estradiol Estrogen receptor positive 55 26 synthesis. The difference between groups is significant by Wilcoxon rank test Estrogen receptor negative 11 18 (p< 0.001). solute. This effect was largely accounted for by the association comparisons of adipose tissue and breast cancer have always of aromatase with estrogen receptors, all tumors with aroma- shown higher biosynthesis of estrogen in tumor (3, 22). Fur tase activity responding to treatment also being estrogen re thermore, using the methods of the present studies, biosyn thesis of estrogens from dehydroepiandrosterone, A"-andros- ceptor positive. It was also of interest to examine the relationship between tenedione, and testosterone was consistently below detectable tumor aromatization and response to specific therapies which levels in adipose tissue. The large mass of fat in the body may might be active against aromatization. The results are pre compensate for its low synthetic activity and make it the major sented in Table 2, both for adrenalectomy, which removes the source of circulating estrogen in postmenopausal women. However, "on site" tumor production of estrogen may be more major source of C-19 steroid pecursors in postmenopausal women, and for the administration of aminoglutethimide, which important for the growth of the breast cancer. also inhibits tumor aromatase (2). It has been calculated that the MCF-7 cell line of human Although numbers are small, tumors with the greatest in vitro breast cancer might synthesize sufficient intracellular estrogen conversion to estradiol were those which responded while to stimulate estrogen-mediated events (11 ). In the present those without aromatization failed to do so. studies, similar calculations indicate that 0.5 to 12.5 pmol are formed during incubation. This is sufficient to half-saturate estrogen receptor sites in the majority of breast cancers. Discussion However, it should be noted that endogenous levels of testos Our report that human breast cancer may synthesize estro terone in breast tumors are likely to be considerably lower than gen from C-19 steroid precursors (13) has been confirmed by are those used in our incubations (20). On the other hand, in several groups (1, 4, 7, 24). When compared with ovarian the breast there are high concentrations of other C-19 steroid production in premenopausal women, the levels of estrogen precursors (18) which breast tumors may convert to testoster synthesized by a tumor may appear insignificant. However, in one or metabolize directly to estrogen (1, 7, 17, 19). postmenopausal women with breast cancer, a
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