Abstract 4793: TRAF2 is required for the survival of ErbB2-transfored mammary tumor cells

TRAF2 regulates signaling pathways downstream of many members of the TNF receptor superfamily, such as TNFR1 and CD40. Recently, we found that TRAF2 also plays an important role in breast cancer cell survival under conditions of endoplasmic reticulum (ER) stress. It is known that TRAF2 knockout (KO) mice die within a week of birth and this lethality can be rescued by KO of TNFα or TNFR1. In order to determine the role of TRAF2 in mammary tumor development and progression, we crossed MMTV-ErbB2 mice (FVB) with TNF-/-/TRAF2-/+ mice (B6), and generated MMTV-ErbB2 (ErbB2), MMTV-ErbB2-TNF-/- (ErbB2/T-KO) and MMTV-ErbB2-TNF-/-/TRAF2-/- (ErbB2/T/T2-DKO) mice all in FVB/B6 mixed background. In 43 weeks, only 1 of 10 ErbB2/T/T2-DKO mice developed a mammary tumor, while 50% of ErbB2 and ErbB2/T-KO mice developed multiple and larger tumors in 30-32 weeks. Interestingly, the tumor derived from the ErbB2/T/T2-DKO mice did not show decreased cyclin D1 expression, nor the tumor cells cultured in vitro show decreased NF-κB activation in response to RANKL. In addition, ErbB2/T/T2-DKO cells formed mammospheres of similar appearance with that of ErbB2 cells in HEMA-coated plates. However, after dispersion of the mammospheres into single cells, ErbB2/T/T2-DKO cells formed dead cell aggregates, while ErbB2 and ErbB2/T-KO cells formed secondary mammospheres, suggesting that the self-renewal capacity of ErbB2/T/T2-DKO cells is impaired. Mechanistic studies reveal that ErbB2/T/T2-DKO cells are sensitive to death caused by ER stress but not by TRAIL or DNA damage, and that this sensitivity is significantly inhibited by knockdown of RIP1. Collectively, these findings suggest that TRAF2 plays a critical role in mammary tumor development and progression by suppressing the pro-death activity of RIP1, and that TRAF2 and RIP1 interaction could be an attractive target for development of new anti-breast cancer drugs. Citation Format: Hasem Habelhah, Yumei Fan, Laiqun Zhang. TRAF2 is required for the survival of ErbB2-transfored mammary tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4793. doi:10.1158/1538-7445.AM2017-4793