Breast Cancer Prevention with Estrogen
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: A full term pregnancy (FTP) before the age 20 is the only safe, natural event that drastically reduces breast cancer risk in women, worldwide. FTP results in similar protection in rats and mice exposed to potent chemical carcinogens. We do not fully understand the reasons for this protective effect. However, studies in women and rats suggest that FTP permanently reduces secretion of some hormones associated with breast cancer in parous females. In attempt to mimic this protective effect in rats, we have developed a short-term (7-21 days) protective hormone treatment (PHT) using pregnancy levels of estrogen. This PHT reduces mammary cancer incidence by over 80% and multiplicity by over 90% in carcinogen exposed rats. We want to optimize and analyze the physiological and molecular bases of this PHT. Our goal is for this PHT to serve as a paradigm for human breast cancer prevention safely and efficiently.
 
 
 
 
 
 
 
 We have developed procedures for the prevention of carcinogen-induced mammary cancers by short term treatment with pregnancy levels of estrogen in rats. This proposal is to extend those finding to determine the exact amount of estrogen necessary to provide protection, determine if the treatment provides persistent protection, determine whether the treatment is effective as an adjuvant therapy, determination of the physiological bases for the protective effect, and perform gene expression studies that would provide the molecular bases for the protective effect and define gene expression patterns that would serve as biomarkers for the efficacy of the hormone treatment. In this proposal we present the novel hypothesis that protection from mammary carcinogenesis is due to a persistent alteration induced by the pregnancy of levels of estrogen in the hypothalamic-pituitary axis, resulting in a decreased hormone promotional environment necessary for frank mammary cancers.
 
 
 
 
 
 
 
 We will use rats, mostly, and only a small number of mice. Both of these rodent models were highly relevant to successful use of tamoxifen for therapy and prevention of breast cancer in women. Basically we will use two groups of rats, nulliparous controls (unprotected) and nulliparous hormone-treated (protected). The protected group of rats will be treated for 1 or 3 weeks with pregnancy levels of estrogen in silastic capsules while the unprotected will receive silastic capsules containing cellulose. These rats will receive a single injection of carcinogen either before or after the treatment. All animals will be palpated weekly for the presence of mammary cancers which will be removed surgically before they reach a size of 2 cm. The rats will be euthanized 9 months after they received the carcinogen treatment. We will compare incidence of tumors, number of tumors per animal and the tumor latency to evaluate the validity of our hypothesis. Gene expression studies will be done in order to identify biomarkers for efficacy.
 
 
 
 
 
 
 
 The proposed study brings together both the rats and mouse model systems to test the applicability of our short term hormone treatment in the prevention of both hormone-dependent and independent types of mammary cancer. This study utilizes an entirely new concept that short-term continuous exposure to pregnancy levels of estrogens can be highly effective in preventing mammary cancers in rats inoculated with a potent carcinogen. The study is also designed to use physiological levels of hormone for a short period to mimic the protective effect of pregnancy in natural conditions. The study could also provide a rational explanation for the protective effect of pregnancy which could be used to generate novel approaches for breast cancer prevention. The study has the potential to generate a chemoprevention procedure, which will be as effective in prevention of mammary cancer as pregnancy or ovariectomy or long-term tamoxifen treatment with no loss of ovarian function.