Am J Stem Cell 2012;1(3):239-252

Original Article
Prenatal modulation of breast density and breast stem cells by insulin-like growth

Chien-I Chang*, Hoi Pang Low*, Li Qiu, William C Strohsnitter, Chung-Cheng Hsieh

Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Obstetrics and
Gynecology, Tufts Medical Center, Boston, MA 02111, USA. *C-I Chang and HP Low contributed equally to this work.

Received October 3, 2012; Accepted November 15, 2012; Epub November 30, 2012; Published December 10, 2012

Abstract: 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. (AJSC1210001).

Keywords: Alveolar bud, birth weight, breast cancer risk, epithelial ducts, fetal origin of disease, flow cytometry, in utero environment,
mammary gland, mouse model, terminal end bud

Address all correspondence to:
Dr. Chung-Cheng Hsieh
Department of Cancer Biology
University of Massachusetts Medical School
364 Plantation Street, LRB 427
Worcester, MA 01605, USA.
Phone: 508-8564780; Fax: 508-8561310
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