Pregnancy levels of estrogen prevents breast cancer
© BioMed Central 2002
Published: 1 October 2003
Pregnancy and lactation with breast feeding at an early age are the only natural phenomena known to drastically reduce the risk for breast cancer in women of all ethnicities worldwide. Parous rats and mice (lacking mammary tumor virus) are also highly protected against chemically induced breast carcinogenesis. Our research goals during the past 10 years have been to define the reason for the highly reduced risk of the parous phenotype to breast cancers as well as to develop safe, inexpensive, mechanism-based hormonal intervention procedures mimicking the protective effects of pregnancy in rats. The first part of our presentation will describe the development of two short-term treatments, modified from Huggins and colleagues' 1962 procedure, with estradiol (E) and progesterone (P) in silastic capsules for 7–21 days. We have acronymed these procedures as short-term E treatment (STET) and short-term E + P treatment (STEPT). These treatments containing late pregnancy levels of E, with or without P, for 7 days are sufficient to reduce the breast carcinoma incidence by over 80% and multiplicity by 90% in rats exposed to the potent carcinogen, N-methyl-N-nitrosourea (MNU). Non-pregnancy or low early pregnancy levels of E were ineffective in protecting rats against MNU-induced breast carcinogenesis. This has been the first demonstration suggesting that the late pregnancy levels of estrogen may be the reason for the protective effect of pregnancy in breast cancer risk reduction. The second part of our presentation will focus on experiments characterizing the parous phenotypes: Why are they protected against breast cancers? Our results show that parous rats are not fully protected; they are susceptible to MNU-induced initiation and develop microscopic latent mammary cancers. These rats are, however, protected from further promotion-progression from developing into overt palpable cancers. Our results also indicate that parous rats have persistently reduced mammogenic hormones, growth hormone and prolactin as well as reduced levels of the receptors for estrogen, progesterone and epidermal growth factor in their mammary epithelial cells. The final section concludes by suggesting that our treatment procedure for breast cancer prevention in carcinogen-treated rats requires only 7 days of treatment (rat gestation 21 days) with no more than 1 μg E/day and is as effective as full-term pregnancy or ovariectomy or prolonged treatment with tamoxifen, without any loss of ovarian function. Our results also suggest that breast cancer protective effects of full-term pregnancy and short-term treatments (STET/STEPT) are due to persistently decreased hormonal environment for promotion-progression of the latent mammary cancers to overt cancers.
Supported by California Breast Cancer Research Program 8PB-0132.