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.
Highlights
Breast cancer is the second-most common and the leading cause of cancer deaths in women in the USA
Mdig is pro-proliferative for noncancerous breast cells To determine basal levels of mdig expression, we measured expression of mdig at the mRNA and protein levels in the noncancerous mammary epithelial cell line MCF10A and six breast cancer cell lines
In the MDA-MB-231 breast cancer cell line, a marginal increase in cell growth was observed 72 h after the silencing of mdig (Fig. 1d). These results indicate that mdig promotes proliferation in noncancerous mammary epithelial cells but not in breast cancer cells
Summary
JmjC domain, a signature motif in the majority of histone demethylases.[4] Emerging evidence suggests a role for mdig in cell proliferation, neoplasias,[3] pulmonary inflammation[5,6] and immune regulation.[7,8] Intriguingly, we previously observed a paradoxical role of mdig in cell proliferation, migration and invasion in cellular experiments.[9] Some environmental factors, including silica, arsenic, and tobacco smoke, induce the expression of mdig, possibly through JNK-STAT3 signaling.[10] Both genetic and epigenetic changes are integral to the complex process of breast carcinogenesis.
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