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Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.

Publication ,  Journal Article
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; Han, H ...
Published in: Mol Ther
April 7, 2021

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.

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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

April 7, 2021

Volume

29

Issue

4

Start / End Page

1541 / 1556

Location

United States

Related Subject Headings

  • Vaccination
  • Th1 Cells
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Proteolysis
  • Interferon-gamma
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Female
  • Cytokines
 

Citation

APA
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Jia, Y., Kodumudi, K. N., Ramamoorthi, G., Basu, A., Snyder, C., Wiener, D., … Czerniecki, B. J. (2021). Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway. Mol Ther, 29(4), 1541–1556. https://doi.org/10.1016/j.ymthe.2020.12.037
Jia, Yongsheng, Krithika N. Kodumudi, Ganesan Ramamoorthi, Amrita Basu, Colin Snyder, Doris Wiener, Shari Pilon-Thomas, et al. “Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.Mol Ther 29, no. 4 (April 7, 2021): 1541–56. https://doi.org/10.1016/j.ymthe.2020.12.037.
Jia Y, Kodumudi KN, Ramamoorthi G, Basu A, Snyder C, Wiener D, et al. Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway. Mol Ther. 2021 Apr 7;29(4):1541–56.
Jia, Yongsheng, et al. “Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.Mol Ther, vol. 29, no. 4, Apr. 2021, pp. 1541–56. Pubmed, doi:10.1016/j.ymthe.2020.12.037.
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. Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway. Mol Ther. 2021 Apr 7;29(4):1541–1556.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

April 7, 2021

Volume

29

Issue

4

Start / End Page

1541 / 1556

Location

United States

Related Subject Headings

  • Vaccination
  • Th1 Cells
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Proteolysis
  • Interferon-gamma
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Female
  • Cytokines