Research Article: Birth Size and the Pathogenesis of Breast Cancer

Date Published: September 30, 2008

Publisher: Public Library of Science

Author(s): Pagona Lagiou, Dimitrios Trichopoulos

Abstract: None

Partial Text: In a major undertaking reported in this issue of PLoS Medicine, a collaborative group co-ordinated by Isobel dos Santos Silva provide all but conclusive evidence that birth size is a predictor of breast cancer risk in adult life [1]. The researchers compiled and reanalysed individual participant data from 32 studies, comprising 22,058 cases of breast cancer. On the basis of reliable data retrieved from birth records, they found that an increase of birth weight by 500 grams was associated with a statistically significant 6% increase in breast cancer risk; whereas, controlling for birth weight, an increase of birth length by two centimetres was associated with a 9% increase in this risk. The relative size of the effects is small, but the individual studies driving the conclusion were of sound epidemiological design (cohort or nested case-control) and relied on objectively documented birth size parameters, allowing little room for selection or information bias. Now that the question of whether birth size is associated with breast cancer risk appears to be settled, a number of additional questions need to be addressed.

In practical terms, a 10% increase in breast cancer risk at the higher birth size category is certainly small, but not trivial for a common disease like breast cancer. Indeed, the gradient is in the same order of magnitude as that found for other common risk factors for breast cancer, such as age at menarche, age at menopause, or postmenopausal obesity [2]. And, from a biological point of view, it is certainly important to document a phenomenon that indicates the involvement of intrauterine processes in a major human cancer, as has already been done in animal models [3].

The observation of sharp ecological contrasts in breast cancer incidence around the world is one of the most challenging features in the epidemiology of the disease, and every hypothesis on the aetiology of breast cancer should be able to accommodate these contrasts. Breast cancer incidence among women of European descent in the Western world is several times higher than that among Chinese or Japanese women in Asia. The gradual elimination of this difference over several generations among Asian migrants in Western countries implies that genetic factors are not responsible for the ecological contrasts [2].

Our current understanding of the early stages in the natural history of breast cancer is limited. Hilakivi-Clarke and de Assis have suggested that epigenetic modifications associated with large birth size lead to modifications in mammary gland development and increased vulnerability of epithelial targets for malignant transformation [3]. It has also been postulated that higher birth size is associated with higher levels of pregnancy hormones, including estrogens and insulin-like growth factor 1, which favour the generation of a higher number of susceptible stem cells with compromised genomic stability [5]. In this context, mammary gland mass, an important determinant of breast cancer risk, could be viewed as an adult life correlate of the number of mammary cells susceptible to transformation [5,6]. The group led by Chung-Cheng Hsieh of the University of Massachusetts is doing important work in this field. This group has reported that high levels of insulin-like growth factor 1 and estriol are associated with larger pools of stem cells in the cord blood [7], and that birth size is also associated with the stem cell pool [8].

Documentation of a positive association of birth size, particularly birth length, with breast cancer risk in adult life may improve prediction of disease risk, but does not offer much opportunity for prevention, particularly since birth size is inversely associated with cardiovascular risk [9]. The situation could change if other periods in early life, particularly postnatal life, were found to be related to adult life breast cancer risk. In any case, recognition of early life influences as critical in the aetiology of breast cancer helps to explain why several adult life primary prevention practices have been of limited effectiveness.

The mammary gland seems to be the only organ that is not fully developed at birth [10], which implies that mammary tissue–specific stem cells may remain in a quiescent stage for longer periods than tissue-specific stem cells for other organs. This could provide an explanation for why intrauterine factors are more important for breast cancer than for other cancers. It is reasonable, however, to expect that intrauterine factors could affect the risk of other forms of cancer, albeit to a lesser extent. In fact, weak birth weight associations have been reported for other cancers, although the evidence is still limited [11].



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