Prenatal modulation of breast density and breast stem cells by insulin-like growth factor-1

Biological determinants of breast density, a strong predictor of human breast cancer risk, are postulated to be influenced by prenatal exposures to mitogens. We investigated the extent to which prenatal exposures to insulin-like growth factor-1 (IGF-1) would affect body weight, breast density, and levels of breast stem/progenitor cells in the prepubescent offspring of wild type C57BL/6J and IGF-1 deficient mice. We found that administration of IGF-1 to pregnant mice resulted in significantly heavier birth and postnatal body weights of the offspring when compared to PBS controls. Morphometric analysis of whole mount carmine alum staining of the left fourth inguinal mammary gland revealed that a prenatal dose of 5 μg IGF-1 resulted in significantly longer ductal elongation in wild type mice and significantly higher breast density in both mouse strains. Furthermore, 5 μg IGF-1 also resulted in the highest number of putative CD49f(+)CD24(+) and CD49f(+)CD24(+)CD29(+) breast stem/progenitor cells in the wild type offspring when compared to PBS controls, as assessed by flow cytometric analysis of dissociated cells from the right fourth inguinal mammary gland, while significantly higher numbers of these cell populations as well as CD24(+)CD29(+) and CD49f(+)EpCAM(+) cells were observed in IGF-1 deficient mice. These findings provide direct evidence for a prenatal modulation of breast density in the offspring by IGF-1, possibly involving populations of breast stem/progenitor cells.