Exploring the Underlying Hormonal Mechanisms of Prenatal Risk Factors for Breast Cancer: A Review and Commentary

Abstract

Prenatal factors have been hypothesized to influence subsequent breast cancer development. Directly evaluating the associations of in utero exposures with risk, however, presents several methodologic and theoretical challenges, including the long induction period between exposure and disease and the lack of certainty regarding the critical timing of exposure. Indirect evaluation of these associations has been achieved by use of proxies such as gestational and neonatal characteristics. Evidence suggests that preeclampsia is associated with a reduced breast cancer risk, whereas high birth weight and dizygotic twinning seem associated with an increased risk. Asians born in Asia have substantially lower breast cancer risks than women born in the West. Although data thus far are few, what exists is not consistent with a unifying hypothesis for a particular biological exposure (such as estrogens or androgens) during pregnancy as mediating the observed associations between pregnancy factors and breast cancer risk. This suggests that additional studies of prenatal factors should seek to broaden the range of hormones, growth, and other endocrine factors that are evaluated in utero. Once candidate biomarkers are identified, assessing them with respect to breast cancer and with intermediate end points in carcinogenesis should be a priority. In addition, investigations should explore the possibility that in utero exposures may not act directly on the breast, but may alter other physiologic pathways such as hormone metabolism that have their effect on risk later in life. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1700 -12)

Birth Weight-Breast Cancer Revisited: Is the Association Confounded by Familial Factors?

“…Finding these factors to be associated with breast cancer has been considered to support a common hormonal pathway (39). However, real evidence to support hormonal pathways, including estrogens, various types of IGFs, and angiogenic factors, have so far been sparse and the findings inconsistent (40). In this study there were no statistically significant associations between zygosity, gestational age, maternal age, or parity, and breast cancer risk.…”

The Relationship between Umbilical Cord Estrogens and Perinatal Characteristics

“…Gestational factors such as preeclampsia, birth weight, and twinning are thought to modify adult breast cancer risk by modifying in-utero estrogen exposure (6,7). Previous studies have questioned the association between these "markers" and direct measures of prenatal estrogens (8), but no previous studies have directly compared prenatal estrogen measures with surrogate markers in large community-based populations. Maternal circulating estrogens have also been used as surrogate markers of fetal estrogen exposure, but there is little correction between maternal and direct fetal measures (9,10).…”

Erratum: Developmental reprogramming of cancer susceptibility

“…Increased birth weight (a surrogate for over-nutrition in utero) positively correlates with increased risk for breast cancer, especially in premenopausal women. By contrast, low birth weight and maternal pre-eclampsia (hypertension, fluid retention, increased weight gain and protein in urine) are associated with decreased breast cancer risk [44][45][46] . High circulating hormone levels at puberty (ascertained by large pelvic intercristal diameter) have been linked to increased breast cancer in daughters 47 , as has prostate cancer risk in sons born before 40 weeks gestation 48 .…”