Epigenome Editing for Targeted Reactivation of X-Linked FOXP3 to Treat Breast Cancers
Abstract
Rationale: The hallmark of cancer includes the genetic mutations in two prominent classes of genes -- oncogenes and tumor suppressor genes. If normal cell physiology is likened to a car, oncogenes represent the accelerator and tumor suppressors represent the brakes. Either malfunctioning brakes or a stuck accelerator can make the car go uncontrollably. Similarly, mutated oncogenes and tumor suppressor genes can cause cells to uncontrollably grow and proliferate, leading to cancer. Human chromosomes come in pairs, with each chromosome carrying one copy (allele) of each gene. Normal human cells contain 22 pairs of autosomal (non-sex) chromosomes and one pair of sex chromosomes. Both autosomal chromosomes in a pair are active, so every cell has two alleles of each autosomal gene. However, males have one X-chromosome per cell (and one Y-chromosome), while females have two X-chromosomes. To keep the X-chromosome gene dose balanced in males and females, one of the X-chromosomes is silenced in females by a process called X-chromosome inactivation. Thus, there is an active and an inactive allele for each X-linked gene in each female cell. Inactivation of tumor suppressor genes on autosomal chromosomes requires mutation of both alleles. In contrast, a mutation of the active allele of an X-linked tumor suppressor is enough to cause cancer because the inactivated allele cannot compensate, even if it is normal. Thus, reactivation of an inactive tumor suppressor allele may be a therapeutic option for treating female breast cancer. Objective: We identified the FOXP3 gene as a tumor suppressor on the X-chromosome in both mice and humans. Expression of the X-linked FOXP3 gene is absent in the tumors of 70% of female patients with breast cancer. Interestingly, most FOXP3 gene mutations are only on the active allele. Based on this observation, we hypothesize that the normal but inactivated allele can be reactivated by new technologies, which will restore breast cancer cells to normal cells. Aims: Our goal is to reactivate FOXP3 gene function for breast cancer therapy in females. First, we will develop a new approach to turn on FOXP3 expression from the inactivated X-chromosome in breast cancer cells. Then, we will observe whether FOXP3 reactivation inhibits breast cancer cell growth in laboratory cells and in an animal model. Second, we will investigate the molecules that allow FOXP3 gene reactivation in breast cancer cells. Significance: One of the most difficult challenges in cancer therapy is to restore the function of inactivated tumor suppressor genes. Thus, our proposed work will provide rationale for new approaches to breast cancer therapy in females, addressing one of the Breast Cancer Research Program s overarching challenges: "Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic." Since loss of FOXP3 occurs in most human breast cancers, this approach may benefit a large population of female patients with breast cancer and FOXP3 defects. Although it will still take time for clinical application of this research, our proposed work should have a long-term impact on developing effective therapies for breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710017
Entities
People
- Lizhong Wang
Organizations
- United States Army
- University of Alabama at Birmingham