Loss of mdig expression enhances DNA and histone methylation and metastasis of aggressive breast cancer

Abstract

We previously reported that expression of an environmentally induced gene, mineral dust-induced gene ( mdig), predicts overall survival in breast cancer patients. In the present report, we further demonstrate the differential roles of mdig between earlier- and later-stage breast cancers. In noncancerous breast, mdig is a proliferation factor for cell growth and cell motility. In breast cancer, however, higher levels of mdig negatively regulate the migration and invasion of cancer cells. Assessment of global DNA methylation, chromatin accessibility and H3K9me3 heterochromatin signature suggests that silencing mdig enhances DNA and histone methylation. Through immunostaining and data mining, we found that mdig is significantly upregulated in noninvasive and/or earlier-stage breast cancers. In contrast, in triple-negative and other invasive breast cancers, diminished mdig expression was noted, indicating that the loss of mdig expression could be an important feature of aggressive breast cancers. Taken together, our data suggest that mdig is a new biomarker that likely promotes tumor growth in the early stages of breast cancer while acting as a tumor suppressor to inhibit invasion and metastasis in later-stage tumors.

Breast cancer: Gene expression influences tumor development

Differential expression of an environmentally-induced gene appears to influence the growth of breast cancer tumors, thus providing a valuable biomarker and therapeutic target. Environmental factors can influence cancerous tumor development by interfering with epigenetic processes such as DNA and histone methylation. For example, the mineral dust induced gene (mdig) is over-expressed in coal miners who are susceptible to lung cancer. Now, Fei Chen, a pioneer in toxicology and carcinogenesis research at the Wayne State University in Detroit, USA, and his team have demonstrated that mdig also plays important roles in breast cancer. The gene is upregulated in early, non-invasive tumors, where it regulates cell growth, motility and invasion by influencing DNA and histone methylation. However, mdig expression drops in later stage or more aggressive tumor types. When the researchers abrogated mdig expression completely, they observed an enhanced DNA and histone methylation, suggesting the gene has a demethylase role and is implicated in regulating the epigenetic landscape under neoplastic conditions.