Inhibition of breast cancer cells by targeting E2F-1 gene and expressing IL15 oncolytic adenovirus.

Yang Yan,Yan Liang,Lingdi Wang,Xin Wu,Wei Wen,Fengyuan Liu,Jiandong Wang,Hu Xu,Xiaohui Du

doi:10.1042/bsr20190384

Abstract

The wide application of oncolytic adenovirus presents a novel therapeutic strategy for breast cancer gene therapy. Application of adenovirus alone achieves little curative effects on breast cancer. In addition, it is worth exploring the synergistic anti-tumor effect by inserting immunomodulatory factor in oncolytic adenovirus genome. By taking the advantage of the highly proliferative property of breast cancer, a novel recombinant adenovirus which could selectively kill tumor cells is established under an E2F-1 promoter. Also by carrying human Interleukin-15 (IL-15) gene, the oncolytic adenovirus exhibits an immunomodulatory effect. The present study proved that the novel oncolytic virus (SG400-E2F/IL-15) exhibits an enhanced anti-tumor activity both in vitro and in vivo, representing an experimental basis for breast cancer “virus-gene” therapy.

Highlights

Breast cancer is well-known as the most common malignant tumor in women [1]
The transcriptional factor E2F-1 plays a significant role in the control of cell cycle, proliferation, and carcinogenesis; a higher expression of E2F-1 is often detected in breast cancer tissues compared with normal tissues [7,8], suggesting that E2F-1 may be an effective target for treatment of breast cancer with oncolytic virus
The results showed that E2F-1 was positively expressed in 45 out of 85 cases (52.9%) of invasive ductal carcinoma (IDC) based on IHC result (Figure 1)

Summary

Introduction

Breast cancer is well-known as the most common malignant tumor in women [1]. Despite the improvement of survival rate due to comprehensive surgical treatment modality, it is still a major challenge treating patients with advanced or recurrent breast cancer [2]. As a new treatment technique, oncolytic adenovirus (a conditionally replicative adenovirus) provides a novel therapeutic modality for breast cancer with its appropriate targeting property [3–5]. To obtain controlled replication of adenovirus, the gene required for adenovirus growth is usually placed under the control of a tumor-specific promoter or enhancer [6]. The transcriptional factor E2F-1 plays a significant role in the control of cell cycle, proliferation, and carcinogenesis; a higher expression of E2F-1 is often detected in breast cancer tissues compared with normal tissues [7,8], suggesting that E2F-1 may be an effective target for treatment of breast cancer with oncolytic virus. Replacement of the endogenous promoter of adenovirus type 5 with the E2F-1 promoter may construct the recombinant adenovirus highly expressed E2F-1 gene in tumor tissues [9,10]

Methods

Results

Conclusion