Hormones of Pregnancy, a-Feto Protein, and Reduction of Breast Cancer Risk

摘要

Parity profoundly reduces breast cancer (BC) risk later in life. It has been reasoned that hormones (either estradiol E_2 or estriol E3), progesterone (P) or human chorionic gonadotropin (hCG) in the serum of pregnant women might lead to that reduction in risk. These agents have been shown to reduce BC incidence in nonpregnant rats. We investigated the hypothesis that exogenously added E_2, E3, P, or hCG are not the proximal effectors of risk reduction, but that they elicit a-fetoprotein (aFP) from the nonpregnant liver, and that aFP is the proximal agent by which reduction of BC risk is obtained. Methylnitrosourea (MNU)-exposed animals were treated with saline, E3, E_2 + P, E3 + P, hCG, or were allowed to experience pregnancy, and AFP levels were measured in the serum and subsequent tumor incidence was recorded. Human HepG2 liver cells in culture were treated with E3, E_2 + P, P, or hCG and elicited AFP was measured in the media. The HepG2 culture media containing elicited AFP was assessed for its ability to inhibit proliferation of T47D cells when applied to these human BC cells in culture, and to inhibit the estrogen-induced phosphorylation of the estrogen receptor in T47D cells. For each condition in the prevention studies, hormone treatment reduced the incidence of BC to an extent similar to that reported by the original studies. In each condition, aFP levels in serum were elevated over that in control animals. In culture, treatment of human liver cells with E3, E_2 + P, or hCG, but not P alone, led to increased levels of AFP in the media. Media containing hCG-elicited AFP inhibited the estrogen-stimulated proliferation of T47D cells in culture, and inhibited phosphorylation of the estrogen receptor, whereas, estrogens and hCG did not inhibit the growth of these tumor cells in culture. In conclusion, since the hormones of pregnancy elicit aFP from the liver, and aFP but not the hormones of pregnancy has direct antitumor properties, it is concluded that aFP is the proximal agent through which reduction in BC incidence is realized from the experience of pregnancy.