Gabriel Sungcad

Background: Breast cancer is one of the leading causes of female cancer mortality, and 15-20% of breast cancer cases involve overexpression of the human epidermal growth factor 2 (HER2) protein.¹ Overexpression of the HER2 protein results in uncontrolled cell growth, which results in tumor development and proliferation.² The standard treatment for HER2-positive breast cancer is administration of the monoclonal antibody trastuzumab, which suppresses HER2 intracellular signaling pathways and promotes antibody-dependent cell-mediated cytotoxicity.^3,4 Trastuzumab resistance, however, is a common complication and has increasingly been attributed to prolonged stability of the HER2 protein.⁵ Ubiquitination pathways regulate HER2 degradation through interactions with E3 ubiquitin ligases, deubiquitinases, and membrane-associated regulatory proteins.⁵ Trastuzumab resistance results from disruption of these pathways, which enable the HER2 protein to avoid degradation and maintain downstream oncogenic signaling.^6,7 Understanding these underlying mechanisms may enable development of new therapeutic strategies capable of enhancing trastuzumab efficacy.^6,7

Objective: This narrative review investigated mechanisms of HER2 ubiquitination that contribute to trastuzumab resistance in HER2-positive breast cancer and explored potential therapeutic targets that regulate HER2 protein stability.

Methods: A literature search was conducted using the PubMed database for studies published between 2022 and 2025. Primary studies analyzing ubiquitination-mediated regulation of HER2 protein stability and downstream implications on trastuzumab resistance were reviewed.

Results: Multiple studies demonstrated how ubiquitination regulation pathways promote HER2 stability and enhance downstream signaling, contributing to resistance against trastuzumab treatment. TRAF4 was found to increase HER2 stability by degrading the E3 ligase SMURF2, resulting in reduced HER2 ubiquitination and sustained downstream signaling.⁶ CAND1 was also found to increase HER2 stability by suppressing CUL7 E3 ligase activity, resulting in reduced HER2 degradation and increased tumor growth.^6,7 In vivo xenograft models exhibited reduced tumorigenesis following downregulation of both TRAF4 and CAND1.^6,7 Deubiquitinases also play important roles in regulating HER2 stability and conferring trastuzumab resistance. USP7 directly removed ubiquitin from HER2, improving stability of the HER2 protein and promoting cellular proliferation and tumorigenesis.⁸ Downregulation of USP7 resulted in reduced HER2 expression and increased apoptosis in HER2-positive cells.⁸ Nuclear HER2 accumulation was also identified as a mechanism of trastuzumab resistance.⁹ PAK5 increased the stability of MALAT1, which enhanced USP8 recruitment and reduced ubiquitin-mediated degradation of nuclear HER2.⁹ Enhanced nuclear HER2 expression was correlated with decreased sensitivity to trastuzumab.⁹ Additionally, CMTM6 was found to directly interact with HER2 and prevent ubiquitination, enhancing HER2 stability and thus trastuzumab resistance.⁵ Altogether, these studies demonstrate that several ubiquitination-related mechanisms operate together to enhance HER2 stability and promote resistance to trastuzumab.

Conclusions: Dysregulation of ubiquitin-mediated degradation pathways is strongly associated with enhanced trastuzumab resistance. The combined activity of E3 ligases, deubiquitinases, and membrane-associated stabilizing proteins enhances stability of the HER2 protein and preserves downstream signaling despite administration of trastuzumab. Targeting ubiquitination modulators such as TRAF4, CAND1, USP7, and CMTM6 may provide novel therapeutic techniques that improve response to trastuzumab treatment and increase personalized treatment approaches. Additional in vivo studies and clinical trials are critical to evaluate the efficacy and safety of therapies targeting HER2 stability.

Works Cited:

1. Martín M. Trastuzumab deruxtecan in breast cancer. Cancer Treat Rev. 2024;126:102733. doi:10.1016/j.ctrv.2024.102733
2. Cheng X, Li J, Li M, et al. A comprehensive review of HER2 in cancer biology and therapeutics. Int J Mol Sci. 2024;25(13):6523. doi:10.3390/ijms25136523
3. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22(2):101-126. doi:10.1038/s41573-022-00579-0
4. Katsura C. Breast cancer: presentation, investigation and management. Hosp Med. 2021;82(11):1-8. doi:10.12968/hmed.2021.0459
5. Xing F, Gao H, Chen G, et al. CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer. Mol Cancer. 2023;22(1):6. doi:10.1186/s12943-023-01716-y
6. Gu Y, Gao H, Zhang H, John A, Zhu X, Shivaram S, Yu J, Weinshilboum RM, Wang L. TRAF4 hyperactivates HER2 signaling and contributes to trastuzumab resistance in HER2-positive breast cancer. Oncogene. 2022;41(35):4119-4129. doi:10.1038/s41388-022-02415-6
7. Xia X, He X, Tang M, et al. CAND1 mediates CUL7-dependent HER2 protein stability to drive breast cancer progression. Breast Cancer Res. 2025;27:211. doi:10.1186/s13058-025-02158-8
8. He X, Xia X, Lei Z, Tang M, Zhang J, Liao Y, Huang H. The deubiquitinase USP7 stabilizes HER2 expression and promotes breast cancer progression. Neoplasia. 2025;66:101192. doi:10.1016/j.neo.2025.101192
9. Zhao X, Li Y, Zhang H, Cai Y, Wang X, Liu Y, Li T, Xu C, Teng Y, Li D, Li F. PAK5 promotes trastuzumab resistance by increasing HER2 nuclear accumulation in HER2-positive breast cancer. Cell Death Dis. 2025;16(1):323. doi:10.1038/s41419-025-07657-2