Author:
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Xu, Keli; Usary, Jerry; Kousis, Philaretos C.; Prat Aparicio, Aleix; Wang, Dong-Yu; Adams, Jessica R.; Wang, Wei; Loch, Amanda J.; Deng, Tao; Zhao, Wei; Cardiff, Robert D.; Yoon, Keejung; Gaiano, Nicholas; Ling, Vicki; Beyene, Joseph; Zacksenhaus, Eldad; Gridley, Tom; Leong, Wey L.; Guidos, Cynthia; Perou, Charles M.; Egan, Sean E.
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Abstract:
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Basal-like breast cancers (BLBC) express a luminal progenitor gene signature. Notch receptor signaling promotes luminal cell fate specification in the mammary gland, while suppressing stem cell self-renewal. Here we show that deletion of Lfng, a sugar transferase that prevents Notch activation by Jagged ligands, enhances stem/progenitor cell proliferation. Mammary-specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling. Human BL breast tumors, commonly associated with JAGGED expression, elevated MET signaling, and CAVEOLIN accumulation, express low levels of LFNG. Thus, reduced LFNG expression facilitates JAG/NOTCH luminal progenitor signaling and cooperates with MET/CAVEOLIN basal-type signaling to promote BLBC. |