Abstract 3496: TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis

TRAF2 plays a key role in the immune response and cell survival by regulating the NF-κB and JNK pathways in response to most members of the TNF superfamily. TRAF2 has also been shown in cell culture systems to mediate IRE1α-induced activation of the ASK1-JNK pathway to promote apoptosis under conditions of acute endoplasmic reticulum (ER) stress. Gene knockout studies revealed that mice deficient for RANKL or NF-κB display defects in osteoclastogenesis and lactating mammary-gland development. Here, we report that TNFα and TRAF2 double knockout (DKO) mice develop with normal bone morphology and density, but the female mice display a severe lactation defect due to significantly increased apoptosis of cells in the lobuloalveolar tree. Unexpectedly, RANKL-induced activation of the canonical NF-κB pathway is not only normal in DKO mammary epithelial cells (MECs), but the expression of the NF-κB target genes is significantly enhanced due to constitutive activation of the non-canonical NF-κB pathway in the absence of TRAF2. On the other hand, cytotoxicity assays revealed that DKO MECs exhibit significantly increased susceptibility to apoptosis induced by chronic ER stress, but not by death receptor or DNA damage. In addition, siRNA-mediated knockdown of TRAF2 in breast cancer cells significantly sensitized the cells to chronic ER stress-induced apoptosis in a RIP1-dependent manner. These data suggest that the physiological function of TRAF2 is to protect the cells from apoptosis under conditions of pathologically relevant chronic ER stress. Given that the lactating MECs and rapidly growing cancer cells have high demands for protein syntheses and ER stress responses, our findings suggest that inhibition of the IRE1α-TRAF2 pathway could be used as a novel adjuvant therapy to treat rapidly proliferating cancer cells. Citation Format: Hasem Habelhah, Laiqun Zhang, Ainiwaer Xialikaer, Ken Blackwell. TRAF2 protects mammary epithelial and cancer cells from endoplasmic reticulum stress-induced apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3496.