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    Research Grants Awarded

    Molecular Mechanisms Responsible for the Neighbor Effect, the Mesenchymal Transition Induced in TGF-beta non-responsive Breast Cancer Cells by Adjacent Epithelial Cells

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    The microenvironment of breast cancer cells plays an important role in cancer progression, metastasis and treatment. One important mediator of cell signaling in the microenvironment is transforming growth factor beta (TGF- beta). TGF- beta is a tumor suppressor because of its anti-proliferative effects on mammary epithelial cells. However, tumor cells frequently loose their ability to be growth inhibited by TGF- beta and, in later stages of tumor progression, TGF- beta promotes cancer development by inducing cell migration and invasiveness. We have discovered a phenomenon we call the “neighbor effect” in which TGF- beta causes normal mammary epithelial cells to impart a pro-migratory, pro-invasive mesenchymal transition to adjacent TGF- beta -non-responsive mammary epithelial cells or to TGF- beta -non-responsive 4T1 murine breast cancer cells. Our hypothesis is that TGF-beta non-responsive cells, including breast cancer cells, can be induced to become more mesenchymal and invasive by interaction with adjacent normal mammary epithelial cells that are responding to TGF-beta. Our specific aims are: 1) to elucidate the molecular mechanisms for this neighbor effect in the mouse mammary cell systems we have already generated and 2) to extend our analysis of the neighbor effect to human breast cancer cell lines. We have established that soluble factors from TGF-beta treated mammary epithelial cells are not sufficient to mediate the neighbor effect observed in co-culture. We will test whether changes in E-cadherin cell-cell adhesion in the TGF- beta responsive cells trigger molecular changes associated with increased ß -catenin signaling and mesenchymal transition in the adjacent TGF-beta non responsive cells. We will examine the roles of seven candidate signaling transduction proteins, previously implicated in epithelial to mesenchymal transition, in mediating the signal or the response involved in the neighbor effect. Finally we will establish the ability of the neighbor effect to cause a mesenchymal transition in human breast cancer cell lines through interaction with TGF-beta activated human mammary epithelial cells. This neighbor effect may contribute to breast cancer progression and metastasis and as such, defining the molecular mechanism for this effect could provide novel therapeutic targets for treating breast cancer.

    Lay Abstract:
    Breast cancer cells arise, grow and metastasize while surrounded by normal cells and tissue. The cancer cells and the normal cells in the tissue interact or communicate in a variety of poorly understood ways that probably have important consequences to whether the cancer cells survive, prosper and metastasize to other sites in the body. We have used a cell culture model system to study an interaction between breast cancer cells, or cells we have modified to act like breast cancer cells, and normal mammary epithelial cells. We have discovered a phenomenon we call the "neighbor effect" in which the adjacent normal epithelial cells help the cancer cells transition to a form that is associated with more invasive or metastatic behavior. The cancer cells probably trigger this assistance from their normal cell neighbors. We propose to learn how this process works at a molecular level. We have identified one important molecule in this interaction, a cell to cell communication protein called transforming growth factor beta (TGF-beta). TGF-beta normally acts as a brake on mammary epithelial cell growth so breast cancers become resistant to this effect in order to grow. Our hypothesis is that TGF-beta non-responsive cells, including breast cancer cells, are induced to become more invasive by interaction with adjacent normal mammary epithelial cells that are responding to TGF-beta. Our specific aims are: 1) to elucidate the molecular mechanisms for this neighbor effect in the mouse mammary cell systems we have already generated and 2) to extend our analysis of the neighbor effect to human breast cancer cell lines. We will test whether changes in cell-cell adhesion in the TGF- beta responsive cells trigger molecular changes associated with increased signaling and transition in the adjacent TGF-beta non responsive cells. We will examine the roles of candidate signal transduction proteins in mediating the signal or the response involved in the neighbor effect. Finally we will establish the ability of the neighbor effect to cause a transition in human breast cancer cell lines through interaction with TGF-beta activated human mammary epithelial cells. This neighbor effect may contribute to breast cancer progression and metastasis and as such, defining the molecular mechanism for this effect could provide novel therapeutic targets for treating breast cancer.