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

Abstract

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.

Tópicos em sinalização celular e bioinformática: Princípios de funcionamento do circuito de sinalização Notch e aprendizagem supervisionada variacional de relevância

“…Because Notch-Jagged signaling is more frequently implicated than Notch-Delta signaling in many aspects of tumor progression [15], our results showing the role of Fringe to inhibit Notch-Jagged signaling corroborate with Fringe being reported as a tumor suppressor in multiple cancers such as prostate, lung and basal-like breast cancer (BLBC) [69,70,71]. Further, loss of Fringe facilitates Notch-Jagged signaling that is critical in the tumorigenesis of BLBCs [69].…”

“…This self-activation is represented by a term (λ J J ) denoting the fold-change in expression due to Figure 3.5D vs. that in Figure 3.5B). Because Notch-Jagged signaling is often implicated in many aspects of tumor progression in multiple cancers [31], our results indicating the tendency of Fringe to inhibit Notch-Jagged signaling are consistent with its recently identified role as a tumor suppressor in prostate cancer, lung cancer and basal-like breast cancer (BLBC) [69,70,71]. Further, loss of Fringe facilitates Notch-Jagged cell-cell signaling that is instrumental in the origin of basal-like tumors [69].…”

“…Among the existing homologues, only Lfng has been shown to be a direct downstream target of NICD [15]; and both Lfng and Mfng, but not Rfng, promotes Notch-Delta signaling [16]. Consistently, both Lfng and Mfng, but not Rfng, has been reported to be a tumor suppressor [69,70,71]. Future models should consider the effect of these different Fringe homologues distinctly instead of collapsing them together.…”

“…We here hypothesize that this effect of inflammation is mediated, at least in part, via the Notch-Jagged signaling. To test this hypothesis, we analyzed the genetic profile of 211 breast cancer patients -140 of which have luminal-like BC subtype -a subtype where Fringe is not lost and Jag1 is not overexpressed, and 71 of which belong to triple-negative or basal-like subtype -a subtype in which Fringe is lost, and stromal cells overexpress Jag1 [69,122].…”

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

“…These findings are supported by Xu et al . (2012) who identified elevated MET signaling and caveolin accumulation in human basal‐like breast tumors. In addition, high MET expression has been shown to be associated with poor patient survival in breast cancer (Ponzo et al ., 2009; Raghav et al ., 2012).…”