Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

By G. Dontu, Kyle W. Jackson, Erin McNicholas, M. Kawamura, W. Abdallah, M. Wicha. Breast Cancer Research, 2004

784 citations recorded by the source corpus.

IntroductionNotch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors.MethodsIn order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists.ResultsUtilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells.ConclusionThese studies suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem cells and progenitor cells, affecting self-renewal and lineage-specific differentiation. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells.

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1. Jane E. Visvader
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5. P. Sansone
6. M. Wicha
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8. N. Takebe

Citations in the corpus

• let-7 regulates self renewal and tumorigenicity of breast cancer cells. (2007, background): “The number of mammospheres reflects the quantity of cells capable of in vitro self renewal, while the number of cells/sphere measures the self-renewal capacity of each sphere-generating cell (Dontu et al., 2003; Dontu et al., 2004).”
• High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. (2005, background): “Hi 26 48% (29-68) 46 mo (23-91) JAG1/N1 22 32% (12-51) 40 mo (19-69) 0.”
• Notch signalling in solid tumours: a little bit of everything but not all the time (2011, background): “Aberrant activation of Notch signalling by a DSL peptide has been shown to increase the self-renewal capacity of normal mammary stem cells, leading to a tenfold increase in mammosphere formatio”
• MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells (2009, unknown): “and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells [10,11,14].”
• Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. (2009, result): “It is possible that Notch-4 mediates the enhanced mammosphere-forming capacity of basal cells induced by Notch ligand (Dontu et al. 2004), but this would differ from findings in the mouse where canonical Notch signaling plays a repressive role.”
• Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways (2011, background): “Notch signaling is also critical for normal hematopoiesis, breast development, colorectal epithelial maturation, immune regulation, and neural stem cell survival”
• Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. (2006, background): “We have previously shown that mammosphere number upon multiple passages reflects stem cell self-renewal, whereas mammosphere size reflects progenitor cell proliferation (9, 10).”
• IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. (2007, result): “This finding supports the notion that N-MS and T-MS from the same individual have different functional properties and that the latter are endowed with an aberrant/defective capacity to differentiate (24).”