Antiestrogen Modulation of the Growth and Properties of Ovarian-Autonomous and Ovarian-Dependent Mammary Tumors in Rats¹

Studies were undertaken to examine the effects of antiestrogens on the growth of two ovarian-autonomous mammary tumors in rats, namely, some dimethylbenz(a)anthracene (DMBA)-induced and ovarian-autonomous tumors in Sprague-Dawley rats and the ovarian-autonomous R3230AC mammary tumor in Fischer 344 rats. Of the approximately 15% of DMBA-induced tumors that continue to grow upon ovariectomy or antiestrogen treatment (250 µg daily s.c. of U 23,469, cis-(3-[p-(1,2,3,4,-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)-phenoxy]-1,2-propanediol) in 0.15 m NaCl, almost all fail to have their growth retarded by subsequent antiestrogen treatment or ovariectomy. However, some DMBA-induced tumors whose growth is stabilized by ovariectomy or by antiestrogen treatment may be further benefited by subsequent treatment with the complementary therapy.

Antiestrogen treatment markedly depresses the growth of the ovarian autonomous R3230AC mammary tumor. Administration of the antiestrogen U 23,469, cis(3-[p(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol) (20 to 250 µg daily s.c. in 0.15 m NaCl) and two related antiestrogens U 11,100A, 1-(2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]ethyl)pyrrolidine hydrochloride and Cl628 α-(4-pyrrolidinoethoxy)phenyl-4-methoxy-α′-nitrostilbene, beginning at the time of tumor transplantation into Fischer 344 host rats results in a 2 to 4-fold depression in tumor growth rate, and the degree of growth reduction is related to the dose of antiestrogen. 17β-Estradiol (15 µg) also depresses R3230AC tumor growth, while growth is at or slightly above the control rate in ovariectomized hosts. During this diminished tumor growth by the antiestrogens cis-(3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)-phenoxy]-1,2-propanediol) and 1-(2-[p-(3,4-dihydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]ethyl)pyrrolidine hydrochloride, cytoplasmic estrogen receptor levels in tumors are below those of the control, and nuclear estrogen receptor levels are elevated. Also, the prolactin and estradiol concentrations in serum do not differ between antiestrogen-treated and control groups. Ovarian-dependent DMBA-induced mammary tumors regressing under antiestrogen treatment show high levels of nuclear and low levels of cytoplasmic estrogen receptor and a marked (approximately 50%) reduction in prolactin receptor level. Ovariectomy also results in a great decrease in the prolactin receptor level of regressing DMBA tumors. These studies document the fact that antiestrogens interact with the estrogen receptor system in R3230AC mammary tumors and slow tumor growth and suggest that antiestrogens may provide palliative benefit in the case of some ovarian-unresponsive but estrogen-sensitive breast cancers.