Breast cancer and the brain: a neurodevelopmental hypothesis to explain the opposing effects of caloric deprivation during the Dutch famine of 1944-1945 on breast cancer and its risk factors.

Most studies on calorie deprivation and cancer risk in rodents show reductions in tumor occurrence. However, the few human studies on calorie restriction are conflicting. An overview is given of results in the DOM (diagnostic onderzoek mammacarcinoom) cohorts among women exposed to the Dutch Famine of 1944-1945. Opposing effects were found on risk factors (shortening of leg length, later menarche, and earlier menopause), whereas urinary estrogens and plasma insulin-like growth factor (IGF)-1 and IGF binding protein-3 were increased, as was breast cancer itself. Exposure between 2 and 10 y old was an unexpected window of susceptibility to the effects of calorie deprivation. The effects of famine exposure were most clearly seen in women who never gave birth. These opposing observations can be explained by a neurodevelopmental hypothesis on set-point shifts at the level of the diencephalons/hypothalamus, either directly or from rebound effects. Such a mechanism reflects old evolutionary adaptation systems in lower and higher organisms to cope with periods of stress and famine by adjusting, for example, reproductive functions. These effects in exposed women may later also affect their unexposed offspring. This hypothesis provides several testable, hormone-mediated corollaries on the relationships between the role of calories in a Westernized lifestyle and human cancer risk. The underlying developmental perspective, as opposed to a risk factor approach, can explain why certain ages, even before breast development, are especially sensitive to effects of large fluctuations in calories. The observations presented may have implications for preventive strategies such as promoting moderation of calorie intake to curb cancer risks.