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Published online on February 25, 2008, 10.1073/pnas.0710535105
PNAS | March 4, 2008 | vol. 105 | no. 9 | 3527-3532


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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Both ovarian hormones estrogen and progesterone are necessary for hormonal mammary carcinogenesis in ovariectomized ACI rats

Edward W. Blank*, Po-Yin Wong*, Rajkumar Lakshmanaswamy{dagger}, Raphael Guzman*, and Satyabrata Nandi*,{ddagger}

*Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California, Berkeley, CA 94720; and {dagger}Department of Pathology, Texas Tech University Health Sciences Center, El Paso, TX 79912

Communicated by Howard A. Bern, University of California, Berkeley, CA, November 14, 2007 (received for review August 3, 2007)

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.

Author contributions: S.N. designed research; E.W.B., P.-Y.W., and R.G. performed research; E.W.B., R.L., R.G., and S.N. analyzed data; and E.W.B. and S.N. wrote the paper.

The authors declare no conflict of interest.

{ddagger}To whom correspondence should be addressed. E-mail: nandi{at}berkeley.edu

© 2008 by The National Academy of Sciences of the USA


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