TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer

Abstract

The HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.

Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

“…Moreover, TRAF4 is the first member of the TRAF protein family to be amplified and overexpressed in multiple human malignancies, including breast, lung, prostate and colorectal cancer, and OSCC [11][12][13]. Several lines of evidence revealed that TRAF4 was not only involved in the initiation and progression of tumors, but also in chemoresistance and radioresistance [12,[14][15][16]. Hao et al identified that TRAF4 was highly expressed in breast cancer and possessed the function of inhibiting apoptosis and promoting cancer cell proliferation via regulating the ubiquitination of spindle assembly-associated protein Eg5 [17].…”

TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance

“…In addition, TRAF4 activated the PI3K/AKT signaling pathway to promote the migration and invasion of hepatocellular carcinoma cells [ 26 ], and clinical evidence suggested that TRAF4 was closely associated with poor prognosis in intrahepatic cholangiocarcinoma [ 27 ]. Overexpression of TRAF4 led to trastuzumab resistance by activating HER2 signaling in HER2-positive breast cancer [ 28 ]. In glioblastoma (GBM), TRAF4 regulates caveolin 1 (CAV1) stability, and drives GBM cell stemness and temozolomide resistance by blocking ZNRF1-mediated ubiquitination and promoting USP7-mediated deubiquitination [ 29 ].…”

Circular RNAs in the chemoresistance of triple‐negative breast cancer: A systematic review

“…Instead, it interacts with tumor necrosis factor receptor‐related factor 4 (TRAF4) and sequesters TRAF4 from activating Eg5 translation, thereby inhibiting Eg5 protein levels (Liu et al, 2018a). Moreover, studies have shown that inhibiting TRAF4 expression in breast cancer cells can reverse tamoxifen and trastuzumab resistance (Gu et al, 2022; Zhou et al, 2020). TRAF4 has been reported to be overexpressed in a variety of cancers, including breast, lung, ovarian, and others (He et al, 2022; Luo et al, 2022; Zhu et al, 2018).…”