Dr. Peter Siegel (left) and Dr. Sébastien Tabariès of the Goodman Cancer Research Centre

By Josh Kaiser

For about 20% to 30% of breast cancer patients, their primary tumour will spread to other organs such as the bones, lungs, liver, or brain. Remarkably, this metastasis to other organs accounts for 90% of deaths during breast cancer treatment. Unfortunately, many of the specific cellular processes regulating breast cancer metastasis are poorly understood and there are currently no targeted treatments.

In a recent paper, published in the journal Genes & Development, scientists at the McGill University Faculty of Medicine’s Goodman Cancer Research Centre (GCRC) have identified potential metastatic biomarkers and a key component of breast cancer metastasis to the liver and lung.

For Dr. Peter Siegel, Associate Professor in McGill’s Department of Biochemistry, member of the Goodman Cancer Research Centre and senior author of the paper, these findings represent a continuation of his research. “Previous work in the lab has identified Claudin-2 as a mediator of breast cancer liver metastasis. We sought a better understanding of its role and the identification of any potential partners important for its ability to promote liver metastasis.”

Based on recent discoveries, the Claudin family of proteins has become particularly interesting to researchers because of their interaction with the tight junctions holding cells together and their importance to the metastatic cascade. To understand this protein further, the paper’s lead author, Dr. Sébastien Tabariès, a research associate in Dr. Siegel’s lab, studied the PDZ-binding motif of Claudin-2, a domain that mediates binding to cytoplasmic-scaffolding proteins. By generating a variant of Claudin-2 that lacks the PDZ-binding motif, the team was able to learn valuable information about its role in liver metastasis.

In particular, they found that breast cancer cells needed the PDZ-binding motif of Claudin-2 for anchorage-independent growth and efficient breast cancer metastasis to the liver, but not for direct interaction with hepatocytes (liver cells). This is significant because one of the hallmarks of cancer metastasis is being able to grow without being anchored to the basement membrane.

Since Claudin-2 is unlikely to act alone in the metastatic cascade though, the researchers also looked for protein interactions. From over one hundred potential candidates, the protein Afadin was selected for further study. Similar to Claudin-2, loss of Afadin in breast cancer cells leads to a reduction in liver metastasis. Surprisingly, both Claudin-2 and Afadin were observed to increase lung metastasis as well. “A new role for Claudin-2 in lung metastasis emerged from this study,” says Dr. Tabariès. “We previously thought that Claudin-2 might be more specific to the promotion of liver metastasis.” Loss of Afadin in particular lead to a 57-fold reduction in lung metastasis. Importance to both liver and lung metastasis suggested a potential use as biomarkers.

With clinical application as the end goal, both proteins were tested for their effectiveness as a predictive biomarker of breast cancer metastasis. In 206 human metastatic breast cancer tumours, higher Claudin-2 expression was associated with increased liver-specific metastases and lower breast cancer specific survival (BCSS), with only a trend in lung-specific metastases. High Afadin expression, on the other hand, had increased lung-specific metastases and lower BCSS, with only a trend in liver-specific metastases.

By defining important cancer specific biomarkers and exploring necessary proteins, this research has given clear direction to breast cancer patients in great need of targeted treatment.

“Afadin co-operates with Claudin-2 to promote breast cancer metastasis,” by Sebastien Tabariès, Peter Michael Siegel, was published in the February issue of Genes & Development. http://www.genesdev.org/cgi/doi/10.1101/gad.319194.118.

April 4, 2019