A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy

Abstract

Parity in women is associated with reduced lifetime risk of breast cancer, and hormones of pregnancy [estrogen (E), progesterone (P), human chorionic gonadotropin (hCG)] are implicated. Parity also reduces mammary cancer risk in carcinogen-exposed rats, and administering pregnancy hormones to these animals is similarly effective. Because pregnancy hormones are also able to stimulate cancer growth, we proposed to resolve this dichotomy by determining whether administered pregnancy hormones elicit the cancer-inhibiting agent α-fetoprotein (AFP) from the liver, which would implicate AFP as a proximal effector of hormonal anticancer activity. Accordingly, we treated groups of nitrosomethylurea-exposed rats with saline, E 3 , E 2 + P, E 3 + P, hCG, or allowed them to experience pregnancy, and then monitored mammary cancer incidence and serum levels of AFP over time. Each hormone treatment reduced mammary cancer incidence and elevated serum AFP levels. To challenge human tissues, human HepG2 liver cells in culture were treated with the same hormonal agents. Each hormone regimen increased the levels of AFP in the culture medium. Medium containing AFP elicited by hCG inhibited the E 2 -stimulated proliferation of cultured human MCF7 breast cancer cells, whereas hCG alone did not inhibit their growth. Furthermore, antibodies to AFP neutralized the growth-inhibiting effect of AFP-containing HepG2 medium. We conclude that in the treatment of carcinogen-exposed rats with the hormones of pregnancy, and by inference in women who have experienced pregnancy, that AFP is a proximal agent that inhibits mammary gland cancer. Cancer Prev Res; 3(2); 212-20. ©2010 AACR.

Free β-human Chorionic Gonadotropin, Total Human Chorionic Gonadotropin and Maternal Risk of Breast Cancer

“…In addition to hCG, other pregnancy hormones are believed to plan an important role in the protection conferred by pregnancy on maternal breast cancer risk. Studies have shown that α-fetoprotein (AFP) may also have a protective effect on maternal breast cancer risk [30]. AFP binds to estradiol and prevents estrogen-dependent growth of breast cancer cells [31].…”

Design and synthesis of biologically active peptides: A ‘tail’ of amino acids can modulate activity of synthetic cyclic peptides

“…AFPep was derived from the naturally occurring protein α-fetoprotein (AFP) [16, 29, 30] which is produced during fetal development [4, 5, 21] and which exhibits anti-oncogenic activity [23]. AFP is reported to be the primary agent responsible for a decreased incidence of breast cancer in populations of women who have experienced a full-term pregnancy compared to the nulliparous population [22, 24, 37].…”

Development of an Active Site Peptide Analog of α-Fetoprotein That Prevents Breast Cancer

“…The pregnancy-based epidemiologic considerations of the effect of AFP in breast cancer, together with the laboratory and clinical observations that AFP has activity against cancer (and especially breast cancer), were brought together to call attention to the centrality of AFP as an anticancer protein (42). Over the years, investigators had proposed various hormones of pregnancy (e.g., estradiol, estriol, androstendione, testosterone, progesterone, chorionic gonadotropins) as the agent responsible for the pregnancy-associated reduction in risk of breast cancer later in life.…”

“…Seemingly, a number of different pregnancy-associated endocrine substances are effective surrogates for parity in terms of reducing mammary cancer risk, but there had been no reasonable explanation of why these diverse treatments should lead to the same outcome. Jacobson and colleagues (42) repeated the studies of the earlier investigators, duplicating their methods of treating carcinogen-exposed rats with estradiol plus progesterone, estriol plus progesterone, estriol alone, or chorionic gonadotropin. In each case, serum levels of AFP were elevated as a result of exposure to the various hormones of pregnancy while tumor incidence decreased.…”

“…Addition of antibodies to AFP (but not to gonadotropin) neutralized the proliferation-inhibiting effect of AFP-containing media. Jacobson therefore proposed a unified mechanism for the reduction of breast cancer risk by the hormones of pregnancy (42), namely that neither estradiol, estriol, progesterone nor chorionic gonadotropin is the proximal inhibitor of breast cancer as had been asserted (43)(44)(45)(46)(47) but rather that these agents act on the liver to elicit production of AFP and that AFP is the proximal mediator of reduction of breast cancer risk. The conclusion is that in the treatment of carcinogen-exposed rats with the hormones of pregnancy and by inference in women who have experienced pregnancy, AFP is the proximal agent that inhibits breast cancer.…”