Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.
Journal Article (Journal Article)
HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
- Jia, Y; Kodumudi, KN; Ramamoorthi, G; Basu, A; Snyder, C; Wiener, D; Pilon-Thomas, S; Grover, P; Zhang, H; Greene, MI; Mo, Q; Tong, Z; Chen, Y-Z; Costa, RLB; Han, H; Lee, C; Soliman, H; Conejo-Garcia, JR; Koski, G; Czerniecki, BJ
- April 7, 2021
Volume / Issue
- 29 / 4
Start / End Page
- 1541 - 1556
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States