Functional characterization of FBXW7 mutations in endometrial cancer

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NHGRI	GEN-5

* FARE Award Winner

Authors

• B. Hong
• M.L. Rudd
• D.W. Bell

Abstract

Serous endometrial carcinoma (EC) is a clinically aggressive subtype of endometrial cancer. We recently discovered that the tumor suppressor gene FBXW7, encoding a ubiquitin ligase, is frequently mutated in serous ECs, suggesting that FBXW7 mutations may drive their development. FBXW7 substrates, Cyclin E1, MCL-1 and c-MYC, are putatively amplified in about 20% of serous ECs, indicating that their de-regulation may be important in these tumors. To determine whether FBXW7 mutations impair the degradation of Cyclin E1, MCL-1 and c-MYC in EC, we measured their stability in FBXW7 mutant and wild-type EC cell lines. Moreover, the effect of FBXW7 knock-down on substrate levels was examined. Our preliminary findings suggest that c-MYC, MCL-1, and possibly Cyclin E1 are more stable in FBXW7 mutant EC cells compared with wild-type EC cells. Consistent with these findings, our preliminary data also suggest that depletion of wild–type FBXW7 in EC cells results in elevated c-MYC, MCL-1, and Cyclin E1 protein levels. In ongoing studies we aim to determine whether recurrent FBXW7 mutations we uncovered in serous EC are dominant-negative or loss-of-function mutants. In conclusion, our preliminary investigations suggest that FBXW7 mutations in EC may result in dysregulation of c-MYC, MCL-1 and Cyclin E1 oncoproteins.

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