Senior Authors' Reply to Invited Commentary: "Beyond the Twinning Effect"

Abstract

We thank Dr. Thompson for his thoughtful commentary (1) on our paper (2), which analyzed the relation of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent risk of breast cancer. He asks whether AFP is a causally relevant variable when assessing breast cancer risk in the women from the Child Health and Development Studies cohort. His answer is yes, because we controlled for the known major risk factors in the etiology of breast cancer although, of course, not all possible causal agents. Because understanding of the biologic actions of AFP has advanced in the few years since we started our study, now there are other compelling data showing that AFP is a factor in the risk of breast cancer. For example, laboratory studies have shown convincingly that the conformation of AFP changes under conditions to which we alluded in our paper, that is, different serum concentrations of hydrophobic ligands such as steroidal estrogens and fatty acids (3). Shock and/or stress events are known to induce conformational changes in the human AFP molecule, exposing a site on the protein that then, in a regulatory fashion, inhibits growth of estrogen-sensitive cells (4). The amino acid sequence for this growth regulatory site has been isolated, purified, and studied in several biologic systems and has shown the capability of suppressing the estrogen-supported growth of breast cancer cells (4, 5). These studies provide evidence of a mechanism for a biologic effect of AFP that was reflected in our data.