Key mechanism identified in metastatic breast cancer

Scientists at the University of Kentucky Markey Cancer Center have identified a key molecular mechanism in breast cancer that enables tumor cells to spread to adjacent or distant parts of the body in a process called metastasis. This finding opens the way to new lines of research aimed at developing treatments for metastatic breast cancer.

The research, led by Peter Zhou, associate professor of molecular and cellular biochemistry at UK, focused on the process by which tumor cells stop clinging to other cells and become motile, or able to spread throughout the body. The findings were published in an article in the EMBO Journal, the flagship publication of the European Molecular Biology Organization.

The increased motility of tumor cells at the initial step of metastasis is similar to a process called epithelial-mesenchymal transition (EMT), which is required for large-scale cell movement in embryonic development, tissue remodeling and wound healing. For example, during wound healing, cells at the edge of the wound undergo a EMT process and migrate to the middle for sealing the wound.

In all EMT processes, cells lose the expression of a cell-to-cell adhesion molecule called E-cadherin, which functions as a “molecular glue” that attaches cells to one another. Breast cancer cells usurp this process for invasion and metastasis. When this molecular glue is broken down, tumor cells start to migrate and spread throughout the body.

A protein called Snail acts as a master switch in the cell's nucleus to suppress E-cadherin expression and induce EMT in the cell. Previous research has shown Snail to be elevated in many types of cancer, particularly breast cancer. High levels of Snail have been linked to metastasis, tumor cell survival and tumor recurrence, and thus predict a poor clinical outcome for women with breast cancer. However, scientists are still not clear how Snail triggers the down-regulation of E-cadherin and induces metastasis in breast cancer.

Using a protein purification approach, Zhou and his colleagues found that Snail interacts and teams up with its “partner in crime,” an enzyme called LSD1, inside the cell. LSD1 is known to change the structure of DNA and shut down the expression of many genes.

LSD1, which stands for lysine-specific demethylase-1 (and is chemically unrelated to the hallucinogen LSD), regulates the structure of the chromosome by removing a key methylation at histone H3, a core component that warps the DNA into compact conformation. This event triggers the “closure” of DNA structure and shuts down gene expression, such as E-cadherin. Zhou's team showed that the N-terminal portion of Snail molecular functions as a “molecular hook” for recruiting LSD1 to the E-cadherin gene, which, in turn, shuts down the expression of E-cadherin and induces tumor cell invasion and metastasis.

“This finding has significant clinical ramification, because chemical compounds or agents that can disrupt the interaction of Snail with LSD1 will have a great therapeutic potential of treating metastatic breast cancer,” Zhou said. “Scientists at the Markey Cancer Center are currently exploring this idea and are keen to develop drugs that can treat metastatic cancer.”

Breast cancer is the most common cancer in women. Approximately 90 percent of breast cancer deaths are caused by local invasion and distant metastasis of tumor cells, and the average survival after documentation of metastasis is approximately two years.

“An understanding of the mechanism underlying the biology of breast cancer metastasis will provide novel therapeutic approaches to combat this life-threatening disease,” Zhou said.

The article, “The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1,” received advance online publication in the EMBO Journal on April 13.