Date Published: April 15, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Yinnan Chen, Yanmin Zhang.
Clinical evidence indicates that drug resistance is a great obstacle in breast cancer therapy. It renders the disease uncontrollable and causes high mortality. Multiple mechanisms contribute to the development of drug resistance, but the underlying cause is usually a shift in the genetic composition of tumor cells. It is increasingly feasible to engineer the genome with the clustered regularly interspaced short palindromic repeats (CRISPR)/associated (Cas)9 technology recently developed, which might be advantageous in overcoming drug resistance. This article discusses how the CRISPR/Cas9 system might revert resistance gene mutations and identify potential resistance targets in drug‐resistant breast cancer. In addition, the challenges that impede the clinical applicability of this technology and highlight the CRISPR/Cas9 systems are presented. The CRISPR/Cas9 system is poised to play an important role in preventing drug resistance in breast cancer therapy and will become an essential tool for personalized medicine.
Breast cancer is one of the main causes of cancer‐related death in women worldwide, accounting for an estimated 28% of new cancers.1, 2, 3 It is a highly heterogeneous disease, and multiple signaling pathways can mediate its initiation and progression.4 According to gene expression profile studies, different subtypes of breast cancer have been identified based on the expression of estrogen receptor (ER) and/or progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). ER belongs to the superfamily of nuclear receptors,5 which played a critical role for development and progression of breast cancer. ER+ disease is one of the most common types of breast cancer, accounting for nearly 70–75% of all cases.6 There are two different molecular forms of the ER, which are ERα and ERβ, coded by different genes, and their expression patterns differ.7 The ER pathway is targeted by endocrine therapies that either repress ER functions or deplete the ligand estrogen, its ligand. While endocrine therapies are very effective, de novo and acquired resistance frequently occurs over the course of therapy.8 The drugs used in the treatment of breast cancer include pharmacological agents for endocrine therapy, such as drugs that target HER2 and other signal molecules, and conventional chemotherapy. The detailed representative drugs of conventional chemotherapy for breast cancer in clinic are listed in Table1.
The conventional way to minimize acquired drug resistance is to combine agents with different targets. However, the mechanisms of action of each drug interact with each other, and the effect is hard to predict. Still another solution is to improve the specificity of the anticancer agent to decrease the possibility of acquired drug resistance, especially for cases of MDR. Additionally, blocking or reversing resistance factors would permit the reuse of existing anticancer drugs.
Drug resistance in breast cancer is complex and involves multiple mechanisms (Figure2). We discuss several key reasons (Notes 1–3) for drug therapy failure in breast cancer, and examine how the CRISPR/Cas9 system overcomes these challenges.
Multiple players within the same mechanism can contribute to cancer drug resistance. Screening and identification of such molecular events may be critical to elucidate the molecular mechanisms inducing resistance to first‐line therapy. Molecular screening of signal pathways regulated in resistant tumor cells could have a major implication in early stage of drug development.2 Comprehensive approaches are required to understand the elements that lead to drug resistance.88
Along with our improved understanding of the mechanisms mediating drug resistance, it is important to select genes that offer the hope of delaying the development of resistance in the treatment of breast cancer. Thus, resistance target screening and identification, as well as reverting resistance gene mutations, with the CRISPR/Cas9 system may provide opportunities to mitigate drug resistance. However, within the CRISPR/Cas9 system, there are still some current limitations.
CRISPR is a revolutionary gene editing strategy that has been rocking the world of biology ever since researchers realized they could apply it to modify the genome of any species with such ease and a precision never achieved before.128 Many recent studies have put this technology into application; for example, the gene‐edited monkey model has been established, as well as a mouse brain engineered with CRISPR/Cas9 system.131 It is a powerful tool and could be used to permanently alter the genome in a manner that could be passed on to future generations. The usage of CRISPR/Cas9 system revives many other social as well as ethical issues, not only for humans but also with other organisms and the environment, such as safety issues to avoid ecological impairment or the technique usage for genetic enhancement. More attention must be placed on risks; especially they may damage living beings and the environment. Meanwhile ethical concerns are raised regarding the possibility of genome editing of the human germline; that is, the genomic information that can be transmitted to following generations, from gametes, a fertilized egg, or first embryo divisions.132 Until now, all therapeutic interventions in humans employing genome editing have been performed in somatic cells. Liang et al. have created concern for the possibility of making changes within the human germline.14
The authors declare no conflict of interest.