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      Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments

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          Abstract

          Introduction

          Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis.

          Methods

          Seven-week-old virgin Lewis rats were given N-methyl- N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7–21 days by subcutaneous implantation of silastic capsules.

          Results

          In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers.

          Conclusions

          The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations.

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          Most cited references57

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          Reproductive factors and breast cancer.

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            Age at first birth and breast cancer risk.

            An international collaborative study of breast cancer and reproductive experience has been carried out in 7 areas of the world. In all areas studied, a striking relation between age at first birth and breast cancer risk was observed. It is estimated that women having their first child when aged under 18 years have only about one-third the breast cancer risk of those whose first birth is delayed until the age of 35 years or more. Births after the first, even if they occur at an early age, have no, or very little, protective effect. The reduced risk of breast cancer in women having their first child at an early age explains the previously observed inverse relationship between total parity and breast cancer risk, since women having their first birth early tend to become ultimately of high parity. The association with age at first birth requires different kinds of etiological hypotheses from those that have been invoked in the past to explain the association between breast cancer risk and reproductive experience.
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              The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth.

              The formation of new blood vessels (angiogenesis) is critical for the growth of tumours and is a dominant feature in various angiogenic diseases such as diabetic retinopathy, arthritis, haemangiomas and psoriasis. Recognition of the potential therapeutic benefits of controlling pathological angiogenesis has led to a search for angiogenesis inhibitors. Here we report that 2-methoxyoestradiol, an endogenous oestrogen metabolite of previously unknown function, is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis in vitro. Moreover, when administered orally in mice, it strongly inhibits the neovascularization of solid tumors and suppresses their growth. Unlike the angiostatic steroids of corticoid structure, it does not require the co-administration of heparin or sulphated cyclodextrins for activity. Thus, 2-methoxyoestradiol is the first steroid to have high antiangiogenic activity by itself. Our results suggest that this compound may have therapeutic potential in cancer and other angiogenic diseases.
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                Author and article information

                Journal
                Breast Cancer Res
                Breast Cancer Research
                BioMed Central (London )
                1465-5411
                1465-542X
                2004
                11 November 2003
                : 6
                : 1
                : R31-R37
                Affiliations
                [1 ]Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California, Berkeley, California, USA
                [2 ]Department of Biology, University of California, Santa Cruz, California, USA
                Article
                bcr734
                10.1186/bcr734
                314450
                14680498
                df6f40ff-66ae-41ad-90e0-58547caa4e2b
                Copyright © 2004 Rajkumar et al., licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                : 8 August 2003
                : 9 September 2003
                : 25 September 2003
                : 9 October 2003
                Categories
                Research Article

                Oncology & Radiotherapy
                cancer,prevention,progestin,estrogen,mammary
                Oncology & Radiotherapy
                cancer, prevention, progestin, estrogen, mammary

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