Hormonal Prevention of Breast Cancer Mimicking the Protective Effect of Pregnancy

Hormonal prevention strategies have used exogenous hormonal treatment to mimic the protective effect of pregnancy against BC. Huggins, et al. (29) reported that high levels of E2 and P given for 30 days beginning 15 days after DMBA administration inhibited MC in SD rats. They proposed that treatment with high levels of these hormones destroyed the potential cancer cells. Grubbs, et al. (30, 31) and McCormick and Moon (32) demonstrated that treatment of SD rats with high levels of and P, or alone following treatment with MNU, a direct acting chemical carcinogen, was as effective as ovariectomy in preventing MC. Grubbs (31) suggested that the primary action of the hormones was to cause differentiation of the pre-neoplastic cells. Recent studies have reported on persistently altered expression of genes in the mammary glands ofparous rats (33). They reported that certain genes involved in growth promotion are persistently down regulated in mammary glands. They also reported that TGF-P3 and several of its transcriptional targets were up regulated. Other investigators studying protection induced by E2 + P treatment have found persistent alterations in the expression of several known genes. Specifically, they have identified persistent changes in and retinoblastoma binding protein (RbAp46), a gene implicated in the regulation of cell proliferation and differentiation following hormone treatment (34, 35).

Russo, et al. (36-39) reported that human chorionic gonadotrophin (hCG) administration before or after DMBA treatment resulted in protection from mammary cancer in SD rats. In 1990 (36), they reported that pregnancy or hCG (100 IU/day) treatment (50-71 days of age), followed by DMBA exposure significantly reduced the incidence ofcarcinomas compared to controls. Srivastava, et al. (23) reported that rats exposed to DMBA on day 45 of age followed by no treatment or hCG treatment from days 65 to 105 resulted in the occurrence of carcinomas in 100% ofthe controls (3.5 cancers/rat), and in 81% ofthe hCG treated (0.9 cancers/rat). This hCG treatment also significantly lowered the incidence of microscopic mammary lesions, intraductal proliferations, and ductal carcinomas in-situ (DCIS). Russo, et al. (36) concluded that hCG treatment, like pregnancy, caused lobular differentiation and that both procedures can efficiently prevent chemically-induced MC.

In an attempt to mimic the protective effect of pregnancy against MC, we have used a modification of the E2 + P treatment, begun earlier by Huggins (29) and confirmed by others (30-32, 40). We were attracted to this mode of treatment because very high levels of E2 are a common feature of pregnancy in all three species. Our modifications included the use of steroids in silastic capsules resulting in sustained constant levels of steroids in the circulation for a short period (7-21 days; gestation period in the rat is 21 days), and assays ofthe blood levels ofthese hormones at the completion ofthe treatment. We also determined the incidence of palpable overt carcinomas, and the incidence of latent mammary cancers by microscopic examination of mammary gland wholemounts.

On the basis of our and our colleagues' studies, we have arrived at an entirely unexpected set of results which have allowed us to generate the following hypothesis regarding the nature of parity protection, and the reason for this protection against mammary cancer in parous rats.

First, our results show that the protective effect of pregnancy is unlikely due to terminal differentiation of TEBs, considered to be the target cells for mammary cancer (10, 11). We now hypothesize that parous females are protected only against promotion-progression and not against initiation. Parous females, treated with carcinogens develop latent microscopic cancers that normally do not undergo promotion-progression to frank carcinomas. A full-term pregnancy results in a persistently reduced promotional environment in parous females which prevents latent cancers from progressing to frank cancers.

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