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. Perou; Sean E. Egan

doi:10.1016/j.ccr.2012.03.041

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

School of Veterinary Medicine

Research output: Contribution to journal › Article › peer-review

76 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 language	English (US)
Pages (from-to)	626-641
Number of pages	16
Journal	Cancer Cell
Volume	21
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2012.03.041
State	Published - 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

Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer. / Xu, Keli; Usary, Jerry; Kousis, Philaretos C.; Prat, Aleix; Wang, Dong Yu; Adams, Jessica R.; Wang, Wei; Loch, Amanda J.; Deng, Tao; Zhao, Wei; Cardiff, Robert; Yoon, Keejung; Gaiano, Nicholas; Ling, Vicki; Beyene, Joseph; Zacksenhaus, Eldad; Gridley, Tom; Leong, Wey L.; Guidos, Cynthia J.; Perou, Charles M.; Egan, Sean E.

In: Cancer Cell, Vol. 21, No. 5, 25.05.2012, p. 626-641.

Research output: Contribution to journal › Article › peer-review

Xu, K, Usary, J, Kousis, PC, Prat, A, Wang, DY, Adams, JR, Wang, W, Loch, AJ, Deng, T, Zhao, W, Cardiff, R, Yoon, K, Gaiano, N, Ling, V, Beyene, J, Zacksenhaus, E, Gridley, T, Leong, WL, Guidos, CJ, Perou, CM & Egan, SE 2012, 'Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer', Cancer Cell, vol. 21, no. 5, pp. 626-641. https://doi.org/10.1016/j.ccr.2012.03.041

Xu, Keli ; Usary, Jerry ; Kousis, Philaretos C. ; Prat, Aleix ; Wang, Dong Yu ; Adams, Jessica R. ; Wang, Wei ; Loch, Amanda J. ; Deng, Tao ; Zhao, Wei ; Cardiff, Robert ; Yoon, Keejung ; Gaiano, Nicholas ; Ling, Vicki ; Beyene, Joseph ; Zacksenhaus, Eldad ; Gridley, Tom ; Leong, Wey L. ; Guidos, Cynthia J. ; Perou, Charles M. ; Egan, Sean E. / Lunatic Fringe Deficiency Cooperates with the Met/Caveolin Gene Amplicon to Induce Basal-like Breast Cancer. In: Cancer Cell. 2012 ; Vol. 21, No. 5. pp. 626-641.

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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.",

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

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AU - Prat, Aleix

AU - Wang, Dong Yu

AU - Adams, Jessica R.

AU - Wang, Wei

AU - Loch, Amanda J.

AU - Deng, Tao

AU - Zhao, Wei

AU - Cardiff, Robert

AU - Yoon, Keejung

AU - Gaiano, Nicholas

AU - Ling, Vicki

AU - Beyene, Joseph

AU - Zacksenhaus, Eldad

AU - Gridley, Tom

AU - Leong, Wey L.

AU - Guidos, Cynthia J.

AU - Perou, Charles M.

AU - Egan, Sean E.

PY - 2012/5/25

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N2 - 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.

AB - 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.

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