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    Awarded Grants
    Investigating the Role of the NFAT Signaling Pathway in Mammary Tumorigenesis

    Scientific Abstract:
    The NFAT family of proteins represents an exquisitely regulated family of latent transcription factors that are known to play an important role in the growth regulation and development of a wide range of tissues and cell types. Intriguingly, recent studies have indicated that deregulation of NFAT activity may play a role in cell transformation and the acquisition of the cancer phenotype. Thus, sustained NFAT activity caused by ectopic expression of a constitutively active NFAT mutant has been shown to be sufficient to transform murine fibroblasts, while human breast and colon carcinoma cell lines have been found to contain high levels of transcriptionally active NFAT activity, that appears to play a role in the regulation of carcinoma invasion and metastasis. In fact, our preliminary data provides evidence that deregulated NFAT activity is also sufficient to induce the normal human mammary epithelial cell line MCF-10A to acquire a transformed cell phenotype and generate aberrant mammary acinar structures that are similar to those observed in human breast ductal carcinoma in situ. Hence, it appears that deregulated NFAT activity is not only involved in the regulation of breast cancer cell metastasis, but can also potentially contribute to the initial events leading to mammary carcinogenesis. Accordingly, the primary goals of this project are first, to investigate the molecular mechanisms underlying the oncogenic potential of deregulated NFAT activity in mammary epithelial cells, and second, to test our hypothesis that deregulated NFAT activity is able to promote mammary tumorigenesis in vivo. In specific aim 1, we will extend our preliminary studies using the well-established MCF-10A 3-D cell culture system to examine the effects of deregulated NFAT activity on cell growth, apoptosis and the ability to undergo normal morphogenesis into growth-arrested mammary acinar structures. In specific aim 2, we will generate transgenic mice expressing a constitutively active NFATc1 mutant under the control of the MMTV-LTR promoter in order to determine the ability of deregulated NFAT activity to promote mammary tumorigenesis in vivo. Collectively, these studies will provide important insights into the role of the NFAT signaling pathway in the regulation of both mammary epithelial cell growth and development and mammary carcinogenesis, and as a result may very well potentially validate this pathway as a prospective drug target in the treatment of breast cancer.

    Lay Abstract:
    The NFAT family of transcription factors is known to play a pivotal role in the regulation of cell growth and development in a number of distinct tissues and cell types. In keeping with their established role in growth control, an accumulating body of evidence has suggested an emerging role for NFAT proteins in the regulation of the cancer phenotype. Thus, deregulated NFAT activity in specific cell types has been found to cause cells to lose normal cellular growth control and acquire the well-established hallmarks of cancer cells. In fact, recent studies have revealed that high levels of active NFAT proteins are present in both human breast carcinoma cell lines and primary human breast tumors, where they appear to play a role in the regulation of cell invasion and metastasis. In addition to this role in the regulation of tumor metastasis, our own preliminary data provides evidence that uncontrolled NFAT activity in mammary epithelial cells can also contribute towards the earliest stages of mammary tumorigenesis. Hence, we believe that the NFAT signaling pathway is likely to play an important role in several distinct aspects of breast cancer including loss of initial growth control, aberrant mammary cell development and increased breast cancer metastasis. Accordingly, our underlying hypothesis is that the NFAT signaling pathway is likely to play an important role in the etiology of breast cancer. To test this hypothesis, we will first perform in vitro experiments using a well-established model cell system of mammary tumorigenesis that will allow us to examine the effects of deregulated NFAT activity on mammary epithelial cell growth and development. Second, we propose to take a genetic approach by developing transgenic mice expressing a constitutively active NFAT mutant specifically in the mammary gland that will allow us to directly test our hypothesis that deregulated NFAT activity can contribute towards the development of breast cancer in vivo. Combined these experiments will afford us significant new insights into the role of the NFAT signaling pathway in the regulation of mammary epithelial cell growth and development, and more importantly, its potential contribution towards the development of breast cancer. Finally, we hope that one of the potential benefits of these studies will be the validation of the NFAT pathway as a potential molecular target for pharmaceutical intervention in the treatment of breast cancer.