Estrous cycle status alters N-methyl-N-nitrosourea (NMU)-induced rat mammary tumor growth and regression

The relationship between mammary carcinoma growth, ovariectomy-induced regression and estrogen receptor status were determined in Sprague-Dawley rats with 5-day estrous cycles after injection of N-methyl-N-nitrosourea (NMU) on metestrus (ME), diestrus-1 (DE-1), proestrus (PE) or estrus (E). Rats exposed to NMU on PE had a shorter tumor latency than those injected on ME and E, as well as more carcinomas per rat than those exposed on ME and DE-1. Mammary carcinomas grew faster in rats injected on ME (doubling time, 6.4 days) and DE-1 (6.9 days) compared with PE (15.2 days) and E (16.3 days). Tumor regression was also significantly faster in rats injected on ME (time to 50% vol., 5.5 days) and DE-1 (5.3 days) compared with PE (8.2 days) and E (8.5 days) following bilateral-ovariectomy during log phase growth. Significantly, total nuclear estrogen receptor (ERN) content was increased in carcinomas from rats injected on PE compared with DE-1 (70.8 +/- 11.3 vs. 32.9 +/- 7.3 fm/mg DNA) (P less than 0.05) and DE-1 and ME combined (P less than 0.01). These observations generalize the concept that estrous cycle stage at the time of NMU injection alters subsequent mammary carcinoma biology, and represents the first experimental evidence that slower growing and responding estrogen receptor positive rat mammary carcinomas may be associated with an increase in circulating estrogen prior to carcinogen exposure.