August-Copenhagen-Irish (ACI) rats are unique in that the ovary-intact females develop high incidence of
mammary cancers induced solely by
hormones upon prolonged exposure to high levels of
estrogen alone. Studies have also shown that such prolonged exposure to high-dose
estrogen results in human-like
aneuploid mammary cancers in ovary-intact ACI rats. To determine the role of
progesterone in mammary
carcinogenesis, six-week-old intact and ovariectomized ACI rats were continuously exposed to low- and high-dose
estrogen alone,
progesterone alone, low-dose
estrogen plus
progesterone, and ovariectomized ACI rats with high-dose
estrogen plus
progesterone. Also, ovariectomized ACI rats were treated with high-dose
estrogen plus
progesterone plus
testosterone to determine the role of the
androgen,
testosterone, if any, in hormonal mammary
carcinogenesis. The results indicate that continuous exposure to high, but not low, concentrations of
estrogen alone can induce mammary
carcinogenesis in intact but not in ovariectomized rats. Mammary
carcinogenesis in ovariectomized ACI rats requires continuous exposure to high concentrations of
estrogen and
progesterone. The addition of
testosterone propionate does not affect
tumor incidence in such rats. These results suggest that both ovarian
hormones estrogen and
progesterone are necessary for mammary
carcinogenesis induced solely by
hormones in ovariectomized ACI rats. Our results are in agreement with the Women's Health Initiative studies, where treatment of postmenopausal women with
estrogen (ERT) alone did not increase the risk of
breast cancer, but
estrogen and
progesterone (HRT) did.