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    The Cellular Basis of Pregnancy-Mediated Protection Against Breast Cancer

    Scientific Abstract:
    Background: A full-term pregnancy is associated with a long-term risk reduction against breast cancer in humans. Parous rats and mice also have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings. To date, the cellular basis and molecular mechanisms for the protective effects of a full-term pregnancy have not been defined. The most widely accepted explanation for this phenomenon is that pregnancy induces the differentiation of target structures for tumorigenesis, i.e. stem cells at duct termini. Recently, we have discovered a new mammary epithelial cell population, which is unique for parous females. This epithelial population originates from differentiating cells during pregnancy and they permanently reside at the terminal end of mammary ducts in the parous gland. Our previous studies have shown that these cells possess two main features of multipotent stem cells: a) self-renewal, and b) contribution to ductal and alveolar morphogenesis. Objective/Hypothesis: We have experimental evidence that parity-induced epithelial cells play an important role in functional adaptation and tissue renewal. A closer examination of these cells might explain differences in tumor susceptibility between mammary tissues from nulliparous and parous females that have been reported earlier. To address this issue, we plan to study the growth properties of the parity-induced epithelial population during normal mammogenesis and, more importantly, in chemically induced mouse models for breast cancer. Specific Aims: (1) To determine whether the parity-induced epithelial cells have all known characteristics of multipotent mammary stem cells; (2) to determine whether parity-induced mammary epithelial cells are resistant to chemically induced carcinogenesis; and (3) to determine the gene expression profile in parity-induced epithelial cells. Study Design: Using a genetic labeling approach to purify parity-induced epithelial cells, we will study in more detail the stem-cell-like properties of this newly discovered cell population. Second, we will examine the cancer susceptibility of parity-induced epithelial cells in a carcinogen-mediated mammary cancer model that has been shown to appropriately recapitulate the effects of pregnancy on mammary tumorigenesis. Third, we will use the methodology of genomics to assess the gene expression profile of parity-induced epithelial cells. Changes in the expression of individual genes that mediate hormone response or trigger differentiation might provide important insights into the nature of pregnancy-related changes and intrinsic effects of mammary epithelia on cancer susceptibility. Potential Outcomes and Benefits of the Research: The proposed studies might contribute to a better understanding of the cellular basis and molecular mechanisms for the protective effects of a full-term pregnancy against chemically induced carcinogenesis in the mammary gland. In the long-term, the identification of differentially expressed genes in parity-induced epithelial cells could serve as biomarkers to characterize this unique epithelial population in other mammalian systems such as normal and malignant human breast epithelial cells and to identify common molecular pathways that convey resistance to chemical and environmental carcinogens.

    Lay Abstract:
    It is a well-established fact that a full-term pregnancy early in life is associated with a long-term risk reduction for developing breast cancer. At a recent NCI-sponsored workshop “Early Reproductive Events and Breast Cancer,” epidemiologists agreed that the long-term protective effect of young age at subsequent term pregnancies is not as strong as for the first term pregnancy. Despite these epidemiological findings, the cellular basis and molecular mechanisms for the protective effects of a full-term pregnancy have not been defined. For a better understanding of this phenomenon, we use rodent models for breast cancer since it has been shown that parous rats and mice also have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings. The most widely accepted explanation for the pregnancy-mediated protection against breast cancer is that pregnancy and lactation induce the differentiation of target structures for tumorigenesis at the terminal end of mammary ducts. Using a genetic labeling approach in mice, we have recently discovered a new mammary epithelial cell population, which is unique for single-parous and multi-parous females. This epithelial population, which possesses stem-cell-like characteristics, originates from differentiating cells during the first full-term pregnancy, and they permanently reside at the terminal end of mammary ducts in the non-pregnant state of the parous gland. This proposal aims to determine whether these pregnancy-induced epithelial cells are resistant to chemicals that trigger breast cancer. We will further investigate the stem-cell-like features of these cells and their gene expression profile. Eventually, we hope to find differences in the expression of individual genes in this unique mammary epithelial cell population that might be associated with the pregnancy-mediated protection against breast cancer.