Correlation of umbilical cord blood hormones and growth factors with stem cell potential: implications for the prenatal origin of breast cancer hypothesis

Todd M Savarese,William C Strohsnitter,William Okulicz,Chung-Cheng Hsieh,David P Chelmow,Inkyung Baik,Kenneth L Noller,Peter J Quesenberry,Qin Liu,Pagona Lagiou,Hoi Pang Low

doi:10.1186/bcr1674

Abstract

IntroductionPrenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis. We examined in umbilical cord blood the correlation of potential breast epithelial mitogens, including hormones and growth factors, with hematopoietic stem cell concentrations serving as surrogates of overall stem cell potential.MethodsWe analyzed cord blood samples from 289 deliveries. Levels of hormones and growth factors were correlated with concentrations of stem cell and progenitor populations (CD34+ cells, CD34+CD38- cells, CD34+c-kit+ cells, and granulocyte–macrophage colony-forming units). Changes in stem cell concentration associated with each standard deviation change in mitogens and the associated 95% confidence intervals were calculated from multiple regression analysis.ResultsCord blood plasma levels of insulin-like growth factor-1 (IGF-1) were strongly correlated with all the hematopoietic stem and progenitor concentrations examined (one standard-deviation increase in IGF-1 being associated with a 15–19% increase in stem/progenitor concentrations, all P < 0.02). Estriol and insulin-like growth factor binding protein-3 levels were positively and significantly correlated with some of these cell populations. Sex hormone-binding globulin levels were negatively correlated with these stem/progenitor pools. These relationships were stronger in Caucasians and Hispanics and were weaker or not present in Asian-Americans and African-Americans.ConclusionOur data support the concept that in utero mitogens may drive the expansion of stem cell populations. The correlations with IGF-1 and estrogen are noteworthy, as both are crucial for mammary gland development.

Highlights

Prenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis
Cord blood plasma levels of insulin-like growth factor-1 (IGF-1) were strongly correlated with all the hematopoietic stem and progenitor concentrations examined
A second tenet is that individuals with relatively elevated in utero/perinatal levels of growth factors (for example, insulinlike growth factor-1 (IGF-1)) and hormones that act as mammary epithelial cell mitogens will have relatively large and mitotically active pools of breast stem cells

Summary

Introduction

Prenatal levels of mitogens may influence the lifetime breast cancer risk by driving stem cell proliferation and increasing the number of target cells, and thereby increasing the chance of mutation events that initiate oncogenesis. A stem cell burden theory has been invoked to explain how in utero and perinatal factors might impact lifetime breast cancer risk [7,8,9,10] The tenets of this theory include the following. A second tenet is that individuals with relatively elevated in utero/perinatal levels of growth factors (for example, insulinlike growth factor-1 (IGF-1)) and hormones (for example, estrogens) that act as mammary epithelial cell mitogens will have relatively large and mitotically active pools of breast stem cells. This would increase the probability that oncogenic mutations will occur in one of these cells. There is evidence for malignant breast 'stem' cells with some properties of normal breast stem/progenitor cells, suggesting that the former may be derived from the latter [15]

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