Abstract
Improvements in the detection and treatment of breast cancer have dramatically altered its clinical course and outcome. However, prevention of breast cancer remains an elusive goal. Parity, age of menarche, and age at menopause are major risk factors drawing attention to the important role of the endocrine system in determining the risk of breast cancer, while heritable breast cancer susceptibility syndromes have implicated tumor suppressor genes as important targets. Recent work demonstrating hormonal modulation of the p53 tumor suppressor pathway draws together these established determinants of risk to provide a model of developmental susceptibility to breast cancer. In this model, the mammary epithelium is rendered susceptible due to impaired p53 activity during specific periods of mammary gland development, but specific endocrine stimuli serve to activate p53 function and to mitigate this risk. The results focus attention on p53 as a molecular target for therapies to reduce the risk of breast cancer.
Highlights
The protective effect of pregnancy with respect to breast cancer was documented by Ramazzini over 300 years ago, who noted the higher rates of breast cancer among Catholic nuns
P53 protein is expressed in the quiescent mammary epithelium of nulliparous mice, responses to γ-radiation were marginal until activated by acute administration of a hormonal regimen mimicking the rise in ovarian steroids that precedes ovulation [5]
Sivaraman et al [7] report a sustained activation of p53 function in the mammary epithelium of rats and mice following treatment with a regimen of estrogen and progesterone (E + P) that was effective in inhibiting mammary tumors
Summary
The protective effect of pregnancy with respect to breast cancer was documented by Ramazzini over 300 years ago, who noted the higher rates of breast cancer among Catholic nuns. Sivaraman et al [7] report a sustained activation of p53 function in the mammary epithelium of rats and mice following treatment with a regimen of estrogen and progesterone (E + P) that was effective in inhibiting mammary tumors In this experiment, postpubertal rats and mice were treated with E + P for 21 days to induce mammary gland development that mimics the changes associated with pregnancy. Differentiation alone is unable to activate p53 or to account for the prophylactic effects of E + P treatment on the mammary epithelium These experiments of Sivaraman et al [7] suggest that prophylaxis is mediated by specific hormone receptor pathways (estrogen and progesterone receptors) and that they strengthen the association between p53 activation and chemoprevention
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