Breast cancer is the leading cause of cancer-related deaths in women. While many patients with breast cancer have been successfully treated through hormone therapy, not all breast cancer cells respond to this form of treatment. Some breast cancer cells express the estrogen receptor (ER) and are therefore amenable to anti-estrogen therapy, while other more aggressive breast cancer cells are ER-negative. Qiang Yu at the A*STAR Genome Institute of Singapore and co-workers have now identified a protein called enhancer of zeste homolog 2 (EZH2) that induces inflammatory gene expression in ER-negative cancer cells, but not in ER-positive cancer cells.
EZH2 has long been known as an inhibitor of gene expression by acting as an enzyme that adds repressive marks to genes. However, Yu and his team were surprised that when they downregulated EZH2 in an ER-negative breast cancer cell line, they observed an increase in expression of a number of genes in the NF-κB signaling pathway, a driver of cancer that has been shown to be upregulated in ER-negative cancer cells. The researchers realized that EZH2 accomplished this transcriptional upregulation not by its known enzymatic activity, because an enzyme-deleted EZH2 mutant was still capable of driving NF-κB gene expression, but by forming a complex with the transcriptional activators RelA and RelB.
Yu and his team showed that RelA, RelB and EZH2 bound to each other within ER-negative breast cancer cells, and when the individual proteins were purified and incubated together. Reducing the expression of any of the three proteins in ER-negative breast cancer cells blocked the ability of the cells to invade a tissue culture. The result suggests that the induction of inflammatory gene expression by the RelA, RelB and EZH2 protein complex contributes to cancer aggressiveness in ER-negative cancer cells.
On the other hand, in ER-positive breast cancer cells, ER binds to EZH2 and brings EZH2 to genes in the NF-κB signaling pathway. EZH2 then adds repressive marks to those genes, causing their expression to be downregulated. By reducing the expression of ER or EZH2 in ER-positive cell lines, they found that NF-κB target gene expression went up.
The findings suggest that the ER expression status of a breast cancer could indicate whether inhibition or activation of EZH2 would be more beneficial for breast cancer treatment, and that ER-negative cancer cells may benefit from a therapeutic approach in which binding of EZH2 to RelA and RelB is blocked.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.