Pilot Project 2: The Effects of Endocrine Disruption on the Developing Human Fetal Mammary Gland

The importance of estrogen in the development of the mammary gland and in breast cancer is well known, but the influence of estrogen on the mammary stem cell (MSC) population has received little attention. The embryonic stem cell genes NANOG, OCT4, and SOX2, which are expressed in normal breast stem cells, exhibit decreased expression upon differentiation but are expressed at higher levels in breast tumor cells (1). Over-expression of each stem cell gene reduces estrogen receptor (ER) expression, and increases the number of stem cells and their capacity for invasion, properties associated with tumorigenesis and poor breast cancer prognosis (1). Accumulating evidence suggests that the developing mammary gland is a sensitive organ for estrogen mimicking chemicals, and that early life exposures “sensitize” the mammary gland to an increased risk of breast cancer in later life (2, 3). This “sensitization” is hypothesized to occur due to epigenetic modifications in genes which regulate the growth and differentiation of mammary stem cells. We hypothesize that exposure of the developing mammary gland to estrogenic chemicals leads to changes in gene transcription in the MSC population, which results in a preneoplastic/neoplastic phenotype. The objective of this study will be to examine the effects of maternal exposure to the estrogenic chemicals, Bisphenol A (BPA) and Genistein, at levels comparable to human exposure on development of the human fetal mammary gland and its stem cell population in a nude rat xenotransplant model.

Specific Aims

• Characterize the growth and differentiation of the human fetal mammary gland in a xenotransplant model. We will characterize the growth and differentiation of the human fetal mammary gland in an immunodeficient nude rat xenotransplant model and examine whether the genes involved in human fetal mammary gland development are similar to the genes involved in rodent mammary gland development. We hypothesize that the signaling pathways/genes which regulate human fetal mammary development are largely conserved from the rodent to the human.
• Characterize the growth parameters of the human fetal mammary gland following estrogenic exposures to genistein or bisphenol A. We will examine the expression of putative MSC markers, p21, Musashi-1, Keratin 19, NANOG, OCT4, and SOX2 and steroid receptors in the human fetal mammary gland following exposure to either BPA or genistein. We hypothesize that xenoestrogens alter the MSC population via epigenetic modifications which alter gene transcription of the fetal mammary gland.

Personnel

Mary L. Hixon, PhD
Project Leader
Mary_Hixon@brown.edu
Read profile

Jodie Pietruska, PhD
Project Co-Leader
Jodie_Pietruska@Brown.EDU