Background

Mice have become central to cancer research due to advancements in genetic modification technology. However, significant interspecies physiological differences limit their ability to accurately mimic human diseases. A prime example is estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of breast cancers. Scientists have long attempted to create ER+ breast cancer models in mice by manipulating mouse genes. However, even when the same genetic mutations are introduced, mice often exhibit loss of estrogen receptors or develop tumors that are markedly different from human breast cancers. The lack of precise preclinical models has hindered the development of therapeutics and the elucidation of underlying mechanisms. Rats, which are physiologically and immunologically more similar to humans, have emerged as an alternative. However, rats have not been widely used as disease models due to the difficulty of genome editing and the complexity of embryo manipulation.

Key Findings

A research team led by Professor Xiang Zhang and Dr. Wen Bu at Baylor College of Medicine successfully overcame these challenges by establishing a rat somatic genome editing platform. The key strategy involves injecting adeno-associated virus (AAV) carrying guide RNA (gRNA) and a donor into the ducts of genetically modified rats that express Cas9. This approach ensures that the editing tools reach the mammary cells. The researchers focused on the synergistic effects of specific gene mutations commonly found in human breast cancer. They simultaneously induced the H1047R missense mutation in the Pik3ca oncogene and the deletion of the Tp53 tumor suppressor gene. Rats with both genes manipulated exhibited significantly faster tumor development compared to those with only a single gene edited. This demonstrates that the two gene mutations have a strong oncogenic collaboration relationship. The resulting rat tumors faithfully reproduced the pathological characteristics of human ER+ breast cancer, with intact ductal structures and high expression of estrogen receptors. Functional similarity in response to hormone therapy was also confirmed. This contrasts sharply with the inability to induce ER+ breast cancer using the same manipulations in mice. Furthermore, the research team identified differences in the distribution of immune cells within the tumors. Tumors with Pik3ca mutations and Tp53 deletions showed a large infiltration of neutrophils, while tumors with Nf1 mutations formed an immune microenvironment dominated by macrophages.

Significance and Prospects

This achievement is expected to expand the landscape of oncology research, shifting it away from its mouse-centric focus and towards the use of rats. By enabling the rapid induction of complex mutations through somatic editing, this study has revolutionized the paradigm of animal model creation. In particular, this rat model will play a crucial role in elucidating the mechanisms of drug resistance in ER+ breast cancer, which has been difficult to reproduce in mice. It provides a valuable tool for identifying new targets and developing novel therapies for recurrent breast cancer that is resistant to endocrine therapy. However, there are still challenges to be addressed for practical application. The viral delivery system needs to be further refined to minimize variations in editing efficiency between individuals. Ultimately, research is expected to expand to other difficult-to-model cancers, such as brain tumors and lung cancer, using this platform.