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Estrogen Synthesis in Human Breast Tumor and Its Inhibition by Testololactone and Bromoandrostenedione¹

Department of Breast Surgery and Breast Cancer Research Unit, Roswell Park Memorial Institute, Buffalo, New York 14263

A total of 53 tumors have been examined for estrogen synthesis from androstenedione and assayed for estradiol receptors. It was found that of the 40 tumors that metabolized androstenedione to estrogens, 17 tumors were estradiol receptor negative and 23 tumors were estradiol receptor positive. Of the 13 tumors that did not synthesize estrogens, 7 tumors were receptor negative and 6 tumors were receptor positive. No correlation was found between the ability of the tumor to synthesize estrogens and the presence or absence of estradiol receptors. The inhibition of aromatase enzyme in human breast tumors by ¹-testololactone, testololactone, and 6- and 6ß-bromoandrostenedione was investigated. Estrone and estradiol synthesis from androstenedione was reduced in five tumor incubations by the presence of 0.2 mM ¹-testololactone and testololactone. 6- and 6ß-bromoandrostenedione (2.0 µM) were also shown to block estrogen synthesis in 5 tumors. Furthermore, Lineweaver-Burk plots revealed that all four compounds were competitive inhibitors of androstenedione aromatization. An apparent K_m of the aromatase enzyme for androstenedione of 0.08 µM and a V_max of 23 pmol of estrone synthesized per g tumor per hr were determined for one human breast tumor specimen. The use of an aromatase inhibitor such as gD¹-testololactone in the treatment of breast cancer should be reconsidered. Data from one patient with advanced cancer of the breast, responding to previous oophorectomy and adrenalectomy and treated with large doses of ¹-testololactone, are presented to illustrate the significance of successful treatment by scientific approaches.