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

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• 作者：Keli Xu¹ ; ¹¹ ; Jerry Usary³ ; Philaretos&#160 ; C. Kousis¹ ; Aleix Prat³ ; Dong-Yu Wang⁴ ; Jessica&#160 ; R. Adams¹ ; ⁶ ; Wei Wang¹ ; Amanda&#160 ; J. Loch¹ ; Tao Deng⁵ ; Wei Zhao³ ; Robert&#160 ; Darrell Cardiff⁸ ; Keejung Yoon⁹ ; ¹² ; Nicholas Gaiano⁹ ; Vicki Ling¹ ; ² ; Joseph Beyene² ; ¹³ ; Eldad Zacksenhaus⁵ ; Tom Gridley¹⁰ ; Wey&#160 ; L. Leong⁴ ; Cynthia&#160 ; J. Guidos¹ ; ⁷ ; Charles&#160 ; M. Perou³ ; Sean&#160 ; E. Egan¹ ; ⁴ ; ^{segan@sickkids.ca}
• 刊名：Cancer Cell
• 出版年：2012
• 期刊代码：43_15356108
• 类别：med
• 出版时间：15 May, 2012
• 卷：21
• 期：5
• 页码：626-641
• 文件大小：5826 K

摘要

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Summary

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.