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. 2017 Jan;30(6):571-574.
doi: 10.1111/pcmr.12603. Epub 2017 Jul 4.

FBXW7 inactivation in a BrafV600E -driven mouse model leads to melanoma development

Iraz T Aydin  1   2   3 , Franco Abbate  1   2   3 , Geena Susan Rajan  1   2   3 , Brateil Badal  1   2   3 , Iannis Aifantis  4 , Garrett Desman  1 , Julide Tok Celebi  1   2   3   5
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FBXW7 inactivation in a BrafVSports在线直播 - V600E -driven mouse model leads to melanoma development

"V体育平台登录" Iraz T Aydin et al. Pigment Cell Melanoma Res. 2017 Jan.

Abstract

Human melanocytic nevi driven by BRAFV600E are in a growth-arrested state referred as oncogene-induced senescence. FBXW7 tumor suppressor is mutated in melanomas, but not in benign precursor melanocytic nevi. In order to characterize whether inactivation of FBXW7 in cooperation with BRAFV600E (BrafV637E in the mouse) is sufficient to bypass from the growth-arrested state, we generated a murine model by conditionally silencing Fbxw7 in an established system, Tyr::CreER; BrafCA (or Tyr::CreER; BrafV600E). We show that loss of Fbxw7 in the presence of BrafV600E mutation is consequential and sufficient to drive tumorigenesis VSports手机版. This model provides further evidence that Fbxw7 is a tumor suppressor in the melanocytic lineage, and can serve as a tool for future pre-clinical studies. .

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Figure 1
Figure 1
FBXW7 inactivation together with BrafV600E mutation cooperates in vivo to drive melanoma formation. (A) Survival curves of the mouse cohorts. Animals with tumor size greater than 1 cm3 or at 12 months after birth were euthanized. Log rank test was used for statistical analysis. (B) Representative examples of melanomas in the Tyr::CreERT2; BrafCA/CA; Fbxw7flox/flox mice are indicated. (C) Histology sections of the melanomas stained with hematoxylin and eosin (H&E) and immunohistochemistry for S100 and Ki67 are shown in the micrographs. (D) Tumors from Tyr::CreERT2; BrafCA/CA; Fbxw7flox/flox mice (without the overlying nevus cells and epidermis) were lysed and analyzed for MITF by western blotting. Actin was used as loading control.
Figure 2
Figure 2
mTOR signaling is activated during loss of FBXW7-mediated tumorigenesis. (A) Melanocytic hyperplasia (blue nevus-like clones) from Tyr::CreERT2; BrafCA/CA mice stained with p-S6 (upper panel) and S100 (lower panel) using immunohistochemistry. Positive staining for p-S6 within the follicular epithelium is indicated as an internal control. (B) Melanomas (tumors within the deep portion of the dermis) from Tyr::CreERT2; BrafCA/CA; Fbxw7flox/flox mice stained with p-S6, p-AKT (S473), and S100. Low (upper panel) and high power (lower panel) magnifications are shown..(C) Histologic and immunohistochemistry analysis of lymph nodes from Tyr::CreERT2; BrafCA/CA; Fbxw7flox/flox mice stained with H&E, S100, and Ki67. Representative micrographs are indicated.
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References

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