Susan G Komen  
I've Been Diagnosed With Breast Cancer Someone I Know Was Diagnosed Share Your Story Join Us And Stay Informed Donate To End Breast Cancer
    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract

    Research Grants Awarded

    Characterization of cancer-initiating cells in pregnancy-associated mammary tumorigenesis.

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Pregnancy and reproductive history have a major impact on breast tumorigenesis. It is generally accepted that a full-term pregnancy early in life is associated with a long-term risk reduction against breast cancer. It has also been shown, however, that each gestation increases temporarily (3-5 years) the likelihood for developing breast cancer. Current theories suggest cancer is a disease of stem cells, and therefore it is vital to identify breast epithelial stem cells and their potential function as targets in both therapeutic and preventive applications. We identified a new mammary epithelial cell population, termed parity-induced mammary epithelial cells (PI-MECs), which originates from differentiating cells during pregnancy and permanently populates the involuted parous mammary gland. Upon transplantation, these cells possess stem cell-like features such as self-renewal and contribution to various epithelial subtypes. Additionally, we show that PI-MECs are cancer-initiating cells in an erbB2 overexpression model. The first specific aim of this proposal is to determine the pluripotency of parity-induced epithelial cells and whether they are able to transdifferentiate into other cell types when introduced into the embryonic stem cell niche. The second aim is to determine whether erbB2 overexpressing neoplastic mammary epithelial cells express stem cell markers identical to those identified in PI-MECs. Finally, we will determine differences and similarities in the gene expression profile of normal PI-MECs to mammary tumor cells. To analyze stem cell surface markers and the gene expression profile in neoplastic cells, we have chosen the erbB2 overexpression model based on high similarities to the pathobiology of human breast cancer and the fact that many pregnancy-associated breast cancers express this important biomarker, which is correlated to poor prognosis. Cell lineages positive for these stem cell markers will be injected into immunocompromised recipient mice to test for tumorigenic potential of particular epithelial subtypes isolated from the bulk of a primary tumor. In conclusion, our experiments will verify preliminary findings and expand our knowledge about the role of PI-MECs as the cancer-initiating cell type in pregnancy-associated mammary tumorigenesis. The targeted inhibition of this cell type might be a suitable approach to prevent cancer in women who are at risk of developing pregnancy-associated neoplasms.

    Lay Abstract:
    Breast cancer is the most common cancer among women evidenced by more than 1.2 million people being diagnosed this year worldwide. Pregnancy and reproductive history have a major impact on breast tumorigenesis. It is generally accepted that a full-term pregnancy early in life is associated with a long-term risk reduction against breast cancer. It has also been shown, however, that each pregnancy increases temporarily (3-5 years) the likelihood for developing breast cancer. Most transgenic strains of mice demonstrate pregnancy-associated mammary cancers following a pregnancy. These transgenic models are, therefore, effective in replicating the transient increase in breast cancer risk following a full-term pregnancy. Current theory suggests cancer is a disease of stem cells, and therefore it is vital to identify breast epithelial stem cells and their potential function as targets in both therapeutic and preventive applications. We discovered a new mammary epithelial cell population, termed parity-induced mammary epithelial cells (PI-MECs), which permanently populates the mammary gland. The PI-MECs have been shown to possess stem cell-like features such as self-renewal and contribution to various epithelial subtypes. Additionally, they are the targets for cancer in an erbB2 overexpression model. Our first aim of this proposal is to determine the ability of PI-MECs to form other cell types when introduced into the embryonic stem cell niche. The second aim is to determine whether neoplastic mammary epithelial cells express stem cell markers identical to those previously identified in PI-MECs. Finally, we will determine differences and similarities in the gene expression profile of normal mammary epithelial cells to mammary tumor cells. To analyze stem cell surface markers and the gene expression profile in neoplastic cells, we have chosen the erbB2 overexpression model based on high similarities to the pathobiology of human breast cancer and the fact that many pregnancy-associated breast cancers express this important biomarker, which is correlated to poor prognosis. In conclusion, our experiments will expand our knowledge about the role of these specific mammary epithelial cells as the cancer-initiating cell type in pregnancy-associated mammary tumorigenesis overexpressing erbB2. The targeted inhibition of this cell type might be a suitable approach to prevent cancer in women who are at risk of developing pregnancy-associated neoplasms.