Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer

Keli Xu, Jerry Usary, Philaretos C. Kousis, Aleix Prat, Dong Yu Wang, Jessica R. Adams, Wei Wang, Amanda J. Loch, Tao Deng, Wei Zhao, Robert Cardiff, Keejung Yoon, Nicholas Gaiano, Vicki Ling, Joseph Beyene, Eldad Zacksenhaus, Tom Gridley, Wey L. Leong, Cynthia J. Guidos, Charles M. PerouSean E. Egan

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)626-641
Number of pages16
JournalCancer Cell
Volume21
Issue number5
DOIs
StatePublished - May 25 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Xu, K., Usary, J., Kousis, P. C., Prat, A., Wang, D. Y., Adams, J. R., Wang, W., Loch, A. J., Deng, T., Zhao, W., Cardiff, R., Yoon, K., Gaiano, N., Ling, V., Beyene, J., Zacksenhaus, E., Gridley, T., Leong, W. L., Guidos, C. J., ... Egan, S. E. (2012). Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer. Cancer Cell, 21(5), 626-641. https://doi.org/10.1016/j.ccr.2012.03.041