FRIZZLED7 (FZD7) is a NOTCH3 specific target in human mammary epithelial cells
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Date
2014-09-09
Authors
Sun, Yu Jia
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Abstract
The current paradigm of Notch signaling indicates that upon ligand binding each of the four NOTCH receptors (NRs) indiscriminately form complexes with a DNA binding complex and regulate the transcription of target genes. Knockout mouse models of individual Notch receptors have no mammary phenotype, suggesting that in mouse mammary glands Notch receptors likely have redundant biological functions. Recent evidence however, indicates that signaling through NR3 alone is essential for maintaining the luminal cell differentiation potential of the bipotential human mammary epithelial progenitors. This observation suggests that NRs play non-redundant roles in regulating the growth and differentiation of mammary epithelial cells and that they may have unique target genes. The focus of my thesis is to identify specific, non-redundant target(s) of Notch receptor 3, a member of the Notch signaling pathway. This project led to identification of FRIZZED-7 (FZD7), a trans-membrane receptor in the Wnt signaling pathway, as a specific gene target of Notch receptor 3. I further demonstrate that NOTCH3 and FZD7 are highly expressed in the luminal progenitors compared to the bipotent progenitors, suggesting that the cross-talk between the WNT and Notch signaling may be involved in the luminal cell fate determination in the bipotent progenitor cells. Since Notch and the Wnt signaling are potent mammary oncogenes, understanding their precise roles and mechanisms of action in regulating the normal mammary gland development provides an insight into how their altered expressions can lead to breast cancer or contribute to pre-malignancy lesion. Furthermore, since FZD7 blocking antibodies are currently in clinical trials for colorectal and intestinal cancers, there might be potential therapeutic values for such antibodies in treating recurrent luminal-type breast cancers.
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Keywords
Notch, Breast Development