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Effect of Tamoxifen on Preneoplastic Cell Proliferation in N-Nitroso-N-methylurea-induced Mammary Carcinogenesis¹

Breast Cancer Research Laboratory [M. P. O., J. F. R., J. P. C., N. T. T.] and Department of Pathology [P. P. R.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

N-Nitroso-N-methylurea (NMU) is an effective carcinogen for the induction of mammary carcinoma in the rat. Tamoxifen (TAM), used as a chemopreventive agent to reduce tumor incidence, has been well studied using this model. We have utilized the rat mammary carcinoma model to assess the effect of TAM on preneoplastic changes. Fifty-day-old virgin female Sprague-Dawley rats were randomized by weight and divided into the following five groups: Group 1, normal controls (n = 24); Group 2, TAM (n = 20); Group 3, NMU-short term (n = 24); Group 4, NMU-short term + TAM (n = 26); and Group 5, NMU-long term (n = 23). Seven weeks after the exposure to NMU, rats in Groups 1, 2, 3, and 4 were given injections of [³H]thymidine and sacrificed 4 h later for autoradiographic determination of thymidine labeling index (TLI). The rats from Group 5 were observed for 30 weeks after NMU exposure to confirm mammary tumor development. TLI in both terminal ducts and terminal end buds was modulated by treatment with TAM. Carcinogen administration induced higher TLI relative to the normal controls [18.3 ± 1.8% (SD) versus 15.5 ± 2.1%, P < 0.001] in terminal end buds. The effect of carcinogen on TLI was also apparent in the terminal ducts (15.8 ± 1.1% versus 9.5 ± 1.1%, P < 0.001). TAM administration was able to suppress both constitutive and NMU-induced TLI increases in terminal end buds (15.5 ± 2.1% versus 2.8 ± 1.1% and 18.3 ± 1.8% versus 6.8 ± 1.4%, respectively, P < 0.001). Similar effects were observed in terminal ducts. In addition to its antiproliferative effect on nontransformed mammary tissue, TAM was effective in suppressing NMU-induced mammary tumor incidence and frequency. NMU-induced hyperproliferation is an intermediate stage in NMU carcinogenesis in the rat and is suppressed by TAM. Mammary epithelial hyperproliferation may provide a useful quantitative intermediate end point to evaluate chemopreventive efficacy.

¹ Supported by the Wanda Jablonski Fund and the Claire and Leonard Tow Foundation to M. P. O. and by the NIH Grant R29 CA 44741 to N. T. T.

² To whom requests for reprints should be addressed, at Strang-Cornell Cancer Research Laboratory, Cornell University Medical College, 428 East 72nd Street, Suite 600, New York, NY 10021.

Received 7/23/91. Accepted 1/ 8/92.

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