1. Academic Validation
  2. UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

  • Cancer Chemother Pharmacol. 2021 Oct;88(4):633-642. doi: 10.1007/s00280-021-04303-4.
Jun Hua  # 1 Zhe Zhang  # 2 3 4 Lili Zhang 5 3 4 Yan Sun 5 3 4 Yuan Yuan 6 7 8
Affiliations

Affiliations

  • 1 Department of Neurology & Psychology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, 1 Fuhua Road, Shenzhen, 518033, Guangdong, China.
  • 2 Department of Pathology, Jiangsu Cancer Hospital, Nanjing, 210009, Jiangsu, China.
  • 3 Jiangsu Institute of Cancer Research, Nanjing, 210009, Jiangsu, China.
  • 4 The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
  • 5 Department of Chemotherapy, Jiangsu Cancer Hospital, Nanjing, 210009, Jiangsu, China.
  • 6 Department of Chemotherapy, Jiangsu Cancer Hospital, Nanjing, 210009, Jiangsu, China. yuanyuan810122@hotmail.com.
  • 7 Jiangsu Institute of Cancer Research, Nanjing, 210009, Jiangsu, China. yuanyuan810122@hotmail.com.
  • 8 The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China. yuanyuan810122@hotmail.com.
  • # Contributed equally.
Abstract

Purpose: This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment.

Methods: 32 women diagnosed with primary HER2-positive breast Cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast Cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the Apoptosis index in BT474 cells treated with trastuzumab.

Results: UCP-2 expression was significantly elevated in surgical tumor samples from breast Cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted Apoptosis.

Conclusion: Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast Cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

Keywords

Breast cancer; Genipin; Human epidermal growth factor receptor 2 (HER2); Trastuzumab; Uncoupling protein 2 (UCP-2).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16069
    99.82%, HER2抑制剂