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Estrous Cycle Modification of Rat Mammary Tumor Induction by a Single Dose of N-Methyl-N-nitrosourea¹

Departments of Pharmacology [T. A. R.] and Surgery, Division of Surgical Oncology [C. W. B.], University of Illinois at Chicago; Health Sciences Center, Cook County, and West Side Veterans Administration Hospitals; and the Hektoen Institute for Medical Research [C. W. B.], Chicago, Illinois 60612

The potential of individual stages of the rat estrous cycle to alter the incidence and subsequent behavior of mammary carcinomas induced by a single dose of N-methyl-N-nitrosourea on diestrus, proestrus, or estrus was examined. Mean latencies to first tumor appearance in diestrous, proestrous, and estrous groups were 86, 71, and 69 days, respectively (P < 0.05 diestrus versus proestrus, estrus). Tumor incidence in diestrous rats given injections (73%) was significantly lower than in proestrous (87%) or estrous (89%) animals given injections, as was the mean number of tumors per rat. However, the number of days required for tumors to reach 1 cm in diameter in diestrous animals given injections (13.0) was significantly lower as compared with tumors in rats given injections during proestrus (19.3) or estrus (22.2). In later growth stages, the diestrous tumor doubling time was one-half that of tumors in proestrous rats given injections. Flow cytometric analysis of tumor tissues during midlog and later growth phases did not reveal any significant changes in ploidy or growth fractions between groups. Further, there was no significant difference in tumor cytosol estrogen receptor incidence, affinity (K_d), or content between groups, although tumor cell nuclear receptor for estrogen was higher (38.3 fmol/mg DNA; P < 0.05) in proestrous rats given injections than in diestrous (21.6) or estrous (21.8) animals given injections. These data support the concept that the prevailing hormonal profile of the estrous cycle at the time of tumor initiation modulates the subsequent induction of mammary tumors. Further, the absence of any observed difference in tumor behavior between proestrous and estrous rats given injections suggests that prolactin does not impose an additive or synergistic effect on the initial stage of tumor induction when mammary gland epithelial cell DNA is previously stimulated by estrogen.

¹ This study was supported in part by Grant PO1 CA31827 awarded by the National Cancer Institute, NIH.

² To whom requests for reprints should be addressed, at the Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Health Sciences Center, 840 S. Wood Street, Chicago, IL 60612.

Received 11/26/84. Revised 3/29/85. Accepted 4/ 3/85.