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Characterization of Estradiol, Progesterone, and Prolactin Receptors in Nitrosomethylurea-induced Mammary Tumors and Effect of Antiestrogen Treatment on the Development and Growth of These Tumors¹

MRC Group in Molecular Endocrinology, Le Centre Hospitalier de l'Université Laval, Quebec G1V 4G2, Quebec, Canada

Properties of estrogen and progestin receptors present in cytosol and of prolactin receptors in membrane fractions of nitrosomethylurea (NMU)-induced mammary tumors in the rat were studied. Sucrose gradient analysis and specific studies revealed a similarity to properties of mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA). Dissociation constants (K_D) at 0.32 and 2.33 nM were observed for receptors for estradiol and progesterone, respectively. In addition, prolactin receptors had specificities and binding constants similar to those found in DMBA-induced mammary tumors. The hormonal dependence of these tumors has also been studied in ovariectomized rats and intact rats given injections of antiestrogens. In the first experiment, rats were given injections beginning on the day of the first NMU injection with 11-methoxyethinylestradiol or tamoxifen (1-p-ß-dimethylaminoe-thoxyphenyl-trans-1,2-diphenylbut-1-ene) or were ovariectomized. All treatments resulted in a diminution in the initiation of tumor growth compared to the control group as has been observed for DMBA-induced mammary tumors. In a second experiment, the effect of these same treatments was studied in animals with established tumors. In control rats, there was an increase in tumor number and size, while ovariectomy and tamoxifen or 11-methoxyethinylestradiol treatments resulted in a prevention of further tumor growth, although none of these treatments induced tumor regression as occurs with DMBA-induced mammary tumors. Ovariectomy and tamoxifen significantly reduced specific binding of 17ß-[³H]estradiol and [³H]-17,21-dimethyl-19-norpregna-4,9-diéne-3,20-dione to cytosol of NMU-induced mammary tumors. Hormone receptor levels for estradiol, progesterone, and prolactin in NMU-induced tumors were of a magnitude similar to those observed in DMBA-induced tumors. Antiestrogen treatment did not affect specific binding of ¹²⁵I-labeled ovine prolactin, but ovariectomy did result in a reduction in prolactin binding. Plasma prolactin values were unchanged by ovariectomy or tamoxifen and increased by 11-methoxyethinylestradiol. These results suggest that NMU-induced mammary tumors are more responsive to endocrine treatment coincident with NMU injection but that treatment of established tumors is somewhat less effective.

¹ Supported by a grant from the Medical Research Council of Canada.

² Recipient of a Fellowship from the Medical Research Council of Canada.

Received 10/ 2/79. Accepted 6/ 6/80.