Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis

Abstract

It is well established that pregnancy early in life reduces the risk of breast cancer in women and that this effect is universal. This phenomenon of parity protection against mammary cancer is also observed in rodents. Earlier studies have demonstrated that shortterm administration of estradiol (E) in combination with progesterone mimics the protective effect of parity in rats. In this study, the lowest effective E dosage for preventing mammary cancer was determined. Rats were injected with N-methyl-N-nitrosourea at 7 weeks of age; 2 weeks later, the rats were subjected to sustained treatment with 20 g, 100 g, 200 g, or 30 mg of E in silastic capsules for 3 weeks. Treatments with 100 g, 200 g, and 30 mg of E resulted in serum levels of E equivalent to those of pregnancy and were highly effective in preventing mammary cancer. E treatment (20 g) did not result in pregnancy levels of E and was not effective in reducing the mammary cancer incidence. In another set of experiments, we determined the effect of different durations of E with or without progesterone treatments on mammary carcinogenesis. These experiments indicate that a period as short as one-third the period of gestation is sufficient to induce protection against mammary carcinogenesis. The pioneering aspect of our study in contrast to long-term estrogen exposure, which is thought to increase the risk of breast cancer, is that short-term sustained treatments with pregnancy levels of E can induce protection against frank mammary cancer. B reast cancer is the most common cancer among women worldwide. The incidence of breast cancer in the United States for the year 2000 was estimated to be Ϸ184,200 new cases (1). The epidemiological evidence provides strong support for the concept that environmental, hormonal, and genetic factors affect the risk for development of breast cancer (2-6). Among the various recognized reproductive risk factors are age at menarche, age at first pregnancy, and age at menopause, all of which seem to suggest that endogenous ovarian steroids may profoundly affect the process of carcinogenesis (3,6,7).Various studies reveal that nulliparous women have a higher risk of breast cancer compared with women who have undergone single or multiple pregnancies early in life (8-10). The protective effect of pregnancy is universal, and pregnancy is the only normal physiological condition that consistently prevents breast cancers in all ethnic backgrounds in all countries without known adverse effects (8-10). The phenomenon of parity protection against mammary carcinogenesis is also observed in rats and mice. Moon (11) demonstrated that parous rats exposed to chemical carcinogens developed fewer cancers compared with virgin rats. Earlier Marchant (12) and very recently Medina and Smith (13) have demonstrated that pregnancy provides protection against mammary carcinogenesis in mouse models. Shortterm administration with ovarian steroids [estrogens and progesterone (P)] or human chorionic gonadotropins either before or after carcinogen treatment dec...

Challenges in the Gynecologic Care of Premenopausal Women With Breast Cancer

“…However, newer evidence suggests that the protective effect may be short-term tissue exposure to pregnancy-level estrogen. 94 Physiologically, endogenous hormones contribute to development of the terminal ductal lobular unit in the breast-the site of origin for both benign and malignant breast tumors that result from cellular proliferation. 95 Pregnancy accelerates the development and maturity of terminal ductal lobular units.…”

Annexin-1 Regulates Growth Arrest Induced by High Levels of Estrogen in MCF-7 Breast Cancer Cells

“…Physiologic levels of 17h-E in premenopausal women ranges from 30 to 300 pg/mL midcycle (0.1-1 nmol/L), whereas higher levels of estrogen (100 nmol/L) may be found in pregnant women. Nulliparous women are more susceptible to breast cancer, and it was suggested that short-term exposure to high pregnancy levels of estrogen may in fact reduce mammary carcinogenesis (26), whereas longer-term estrogen exposure to lower concentrations may result in carcinogenesis. Micromolar concentrations of estrogen have been shown to inhibit proliferation of rhesus ovarian surface epithelial cells (27), via the blocking of serum growth factors, activation of the G 1 -phase cell cycle checkpoint, and induction of p21, possibly through the up-regulation of p53.…”

Mammary developmental fate and breast cancer risk

“…In contrast, the effects of E and P given singly were tested to determine the ability of these hormones to induce protection from mammary carcinogenesis in a post-treatment model (Rajkumar et al 2001). It was shown that treatment with E2 alone, at a critical dose of 100 mg/silastic tubing, provided a pregnancy level of circulating E2 and a protection from mammary carcinogenesis compared with the AMV.…”