Pregnancy, p53 and breast cancer risk

BETHESDA — Early pregnancy is known to protect women from breast cancer, but the mechanism by which this is achieved remains unclear. In 23 October Proceedings of the National Academy of Sciences, Lakshmi Sivaraman and colleagues at the Baylor College of Medicine (BCM), Houston, Texas, challenge one leading theory and propose new ideas to explain their unexpected finding that the tumor suppressor gene, p53, seems to have a significant role to play. "Before we started this study, we had no idea this [effect] would turn out to be related to p53," said Bert O'Malley, Chairman of the Michael DeBakey Center at BCM and the senior author on the paper.The puzzle O'Malley and others in the field are trying to solve is why women who have a full-term pregnancy by age 19 have a 50% reduction in their lifetime breast cancer risk. A first pregnancy in the mid-20s appears to have no effect on risk, whereas the incidence of breast cancer increases slightly among women who delay pregnancy until their late 30s. Although the hormonal changes associated with pregnancy have been implicated in this phenomenon, no specific mechanism has been elucidated. Clearly, the ability to define the mechanism behind the protective effect of early pregnancy on breast cancer risk in women could have important therapeutic implications. Although giving young women high doses of estrogen and progesterone to simulate the hormonal changes of pregnancy may not be a safe or reasonable preventive strategy, O'Malley speculates that there may be other approaches involving hormonal therapy or chemical induction that could act on p53 and trigger the mechanism that provides women with permanent resistance to breast cancer. Previous research has replicated the protective effect of early pregnancy in mouse and rat models. Among mice that were pregnant during adolescence, more than 85% will survive subsequent challenge with a carcinogen. In contrast, 100% of the mice that had not had an early pregnancy will die of breast cancer following carcinogen exposure. When O'Malley and colleagues mimicked pregnancy in rats and mice, they observed that high levels of estrogen and progesterone correlate with increased levels of the p53 protein, which seem to block proliferation of mammary epithelial cells when challenged with a carcinogen.An alternative theory — challenged by other findings also reported in the PNAS paper — suggests that early pregnancy induces differentiation of the mammary gland and that the fully differentiated mammary cells are naturally more resistant to carcinogen. O'Malley tested this hypothesis by chemically differentiating the mammary gland in rats using perphenazine (PPZ), a dopamine receptor inhibitor, which stimulates the release of prolactin from the anterior pituitary gland. Although PPZ did cause morphological and functional differentiation of the mammary gland in rats, it did not protect them from the carcinogen.O'Malley concluded, therefore, that cellular differentiation is not a mediating factor in this protective response, and that there is a direct correlation between p53 and chronic resistance to breast cancer. Future studies will attempt to prove a cause-and-effect relationship. Given that the results in the PNAS paper demonstrate no change in p53 gene transcription, but increased p53 levels in the tissue, O'Malley suggests that estrogen and progesterone physically stabilize the p53 protein, preventing its degradation and delaying its natural turnover. "It does not change the rate of gene expression as much as it prolongs the half-life of the protein," says O'Malley, who predicts that post-translational modifications may have a role in this stabilizing effect.The idea that hormones may stabilize p53, giving it a longer half life in the cell, led O'Malley to propose that cells with an elevated level of p53 may be better equipped to repair DNA damage caused by carcinogen exposure. p53 promotes cell cycle arrest, thereby preventing carcinogen-induced cell proliferation. "Timing [of the first full-term pregnancy] is really important," explained O'Malley, and "we would like to know what the timing means." The suspicion is that it relates to the accumulation of DNA damage in adult mammary tissue. In young women, who might not yet have established mutations in mammary cells, high doses of estrogen and progesterone appear to have a protective effect. But, at a later age, once precancerous changes are present, these same sex hormones may aggravate the situation and increase a woman's risk of developing breast cancer. The lifetime risk of breast cancer among Western women is about 10%. Risk factors include a family history of breast cancer, first full-term pregnancy after age 30, absence of pregnancy, early menarche, and delayed menopause. The effects of breast-feeding are not clear, although longer duration of lactation may have a protective effect. According to the US National Cancer Institute, recent studies suggest that long-term oral contraceptive use or estrogen replacement therapy may increase a woman's risk of breast cancer. All of these reproductive factors are believed to affect breast cancer risk as a result of their effects on a woman's hormonal status.Jose Russo and colleagues at the Breast Cancer Research Laboratory at Fox Chase Cancer Center, Philadelphia, described breast cancer as "a classical model of hormone dependent malignancy." (J Mammary Gland Biol Neoplasia 1998, 3:49-61). The authors also state that, "An early first, full-term pregnancy exerts a protective effect, emphasizing the need for understanding the role of reproductive influences on breast development and on cancer initiation and progression, and providing a paradigm for developing preventive strategies based on physiological principles." (Microsc Res Tech 2001, 52:204-223).The goal remains to understand how reproductive hormones can protect against mammary carcinogenesis. The next step for O'Malley's group is to prove the causative role of extended p53 half-life and to elucidate the mechanism by which it confers resistance to mammary carcinogenesis. Then he hopes to search for a way to achieve the same protective effect that can be safely tested in women.

Pregnancy, p53 and breast cancer risk

The age at which a woman becomes pregnant could influence whether she subsequently develops breast cancer.

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