Blank Edward W, Wong Po-Yin, Lakshmanaswamy Rajkumar, Guzman Raphael, Nandi Satyabrata
Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3527-32. doi: 10.1073/pnas.0710535105. Epub 2008 Feb 25.
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.
奥古斯塔-哥本哈根-爱尔兰（ACI）大鼠的独特之处在于，卵巢完整的雌性大鼠在长期单独暴露于高水平雌激素时，仅由激素诱导就会出现高发性乳腺癌。研究还表明，在卵巢完整的ACI大鼠中，这种长期暴露于高剂量雌激素会导致类似人类的非整倍体乳腺癌。为了确定孕酮在乳腺癌发生中的作用，将六周龄的完整和去卵巢ACI大鼠分别持续暴露于单独的低剂量和高剂量雌激素、单独的孕酮、低剂量雌激素加孕酮，以及去卵巢的ACI大鼠给予高剂量雌激素加孕酮。此外，对去卵巢的ACI大鼠用高剂量雌激素加孕酮加睾酮进行处理，以确定雄激素睾酮（如果有的话）在激素性乳腺癌发生中的作用。结果表明，单独持续暴露于高浓度而非低浓度的雌激素可在完整大鼠而非去卵巢大鼠中诱导乳腺癌发生。去卵巢的ACI大鼠发生乳腺癌需要持续暴露于高浓度的雌激素和孕酮。添加丙酸睾酮不会影响此类大鼠的肿瘤发生率。这些结果表明，对于去卵巢的ACI大鼠中仅由激素诱导的乳腺癌发生，卵巢激素雌激素和孕酮都是必需的。我们的结果与妇女健康倡议研究一致，在该研究中，单独用雌激素（ERT）治疗绝经后妇女不会增加患乳腺癌的风险，但雌激素和孕酮（HRT）会。
