DNA methylation and the immune system in breast cancer

Abstract

Breast cancer is the cancer with the highest incidence in women and the most commonly diagnosed. It is estimated that 268,000 cases are diagnosed each year in the U.S. of which about 12.8% of women are affected during their lifetime. Many of these patients tend to have high rates of recurrence, high rates of distant metastasis and a poor survival rate across the various types of breast cancer. Hence, there is a need for improved and rapid diagnosis of breast cancer and more targeted treatment methods. ☐ The tumor microenvironment is associated with cancer cell proliferation, survival and metastasis. It includes a variety of cells including immune cells, inflammatory cells and tumor cells. Recent cancer studies on the interactions between the immune system and tumors has led to speculation that the tumor microenvironment plays a role in tumor recurrence and therapeutic resistance. Tumor growth and progression have been associated with immunosuppressive changes in immune cells, specifically in tumor infiltrating and peripheral blood mononuclear cells (PBMC’s). There is a lack of consensus regarding how the tumor microenvironment affects the immune system with regard to impairing the anti-tumor immune response. Of the many epigenetic mechanisms, DNA methylation has been shown to regulate various immune responses. Therefore, the hypothesis was DNA methylation plays a role in the shift of immune cells from an anti-tumor response to an immunosuppressive response. To test this hypothesis, I investigated the methylation patterns of inflammatory genes in peripheral blood mononuclear cells of women with or without breast cancer. ☐ A panel of genes of inflammatory and immune genes were screened using blood samples from normal patients and patients with invasive breast cancer. To further investigate methylation changes in specific CpG sites in these genes, promoter and enhancer regions were analyzed by methylation specific restriction enzyme PCR and restriction enzymes MSPI and HPAII. Five genes were found to have (TNF-alpha, TYK2, IL-4R, IL17RA and IL-17C) significant differences in methylation level in patients with invasive cancer compared to normal patients. ☐ Our data supports the hypothesis that altered DNA methylation in immune and inflammatory genes occurs in invasive disease. Epigenetic changes in these genes may play a role in the shift of immune cells from an anti-tumor response to an immunosuppressive response. Further study is needed to determine if these changes in methylation load have an impact on anti-tumor immune responses.