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Copper-binding Protein Helps Cancer Cells Spread

Copper-binding Protein Helps Cancer Cells Spread

Copper-binding Protein Helps Cancer Cells Spread

Copper-binding Protein Helps Cancer Cells Spread

The copper-transporting protein Atox1 (illustrated in white) delivers copper (blue) to an enzyme which facilitates breast cancer cells to migrate away from the primary tumor (red) and metastasize towards other parts of the body. Illustration credit: Boid
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Researchers at Chalmers University of Technology have shown that the Atox1 protein, found in higher concentrations in breast cancer cells, participates in the process by which cancer cells migrate. The protein could therefore be a potential biomarker for assessing the aggressiveness of the disease, as well as a possible target for new drugs. The research was recently published in the journal PNAS.
Breast cancer is the most common form of cancer in women worldwide. Early diagnosis and treatment are crucial to the survival rate. Most deaths related to breast cancer are due to cancer cells spreading, that is leaving the primary tumour and metastasising in other parts of the body, such as the skeleton, liver or lungs. But the molecular mechanisms behind how cancer cells migrate to other parts of the body are not yet understood.

Breast cancer coincides with higher levels of copper in the tumours

Previous studies have shown that, like other cancers, breast cancer coincides with higher levels of copper in the blood ​and in tumour cells of the patients, but the use of this extra copper in cancer cells is not known.

​Copper and other metal ions are vital for many biological functions, in small, controlled quantities. Free copper ions are toxic and thus all copper in our body is bound to proteins. Copper is absorbed through food and is then transported to different parts of ​the body by transport proteins. 

​Atox1 is localised at the leading edge of migrating cancer cells​

Re​searchers at Chalmers have now identified a copper-binding protein that clearly influences breast cancer cell migration.

“There are clinical trials where they use copper depletion as a therapeutic strategy, but we focus on the copper-binding proteins as potential targets. Using a database, we first identified all the different copper-binding proteins in humans and then we compared the amount of these proteins in cancerous to healthy tissues. Atox1 was one of the copper-binding proteins with a high concentration in breast cancer cells,” says Pernilla Wittung-Stafshede, Professor of Chemical Biology at the Department of Biology and Biological Engineering.​​​

Atox1 is a so-called copper-transporter, a protein that transports copper to other proteins in our cells which require it for their enzymatic functions. The Chalmers researchers recently found that Atox1 is localised at the leading edge of migrating cancer cells, indicating that the protein may be involved in cell movement. This observation was the starting point for the now published study.

​The researchers tracked the movement of cancer cells

Using advanced live-cell video microscopy, the researchers were able to observe and track the pattern of movement of hundreds of individual cancer cells, with and without the presence of Atox1.

​"Nobody has studied how a copper-binding protein affects migration of breast cancer cells before. This is a high-resolution method and the experimental work has been time consuming, but we got a result that is very pure and informative. We were able to demonstrate that the cells moved at higher speeds and over longer distances when Atox1 was present, compared to the same cells having less of the protein," says Stéphanie Blockhuys, a Postdoctoral Researcher in Chemical Biology, and first author of the study.

​Atox1 drives cell movement

​Further experiments revealed that Atox1 drives cell movement by stimulating a reaction chain consisting of another copper transport protein – ATP7A, and the enzyme lysyl oxidase (LOX). Atox1 delivers copper to ATP7A which in turn delivers the metal to LOX in a synchronised reaction. LOX needs copper in order to function, and it is already known that the enzyme is involved in extracellular processes facilitating breast cancer cell movement.​

​“When Atox1 in the cancer cells was reduced, we found extracellular LOX activity to be decreased. Thus, it appears that without Atox1, LOX does not receive the copper required for its cell migration potential says Stéphanie Blockhuys.

​High Atox1 levels drastically influence survival

​In parallel, the researchers analysed a database of reported Atox1 transcript levels in 1904 different breast cancer patients, along with survival times. They found that patients having tumours with high Atox1 levels have drastically lower survival times. They conclude therefore that the mechanism they identified in their cell culture experiments seems to play a role in the progression of the disease in patients.

This indicates that Atox1 could be a biomarker for assessing how aggressive a breast cancer is. Such information could be used, for example, to determine if treatment to remove copper from the body could be appropriate. Atox1 could also become a target drug for blocking metastasis and thus cancer patient death.

​​“What we have found could be important for all types of cancer. How cancer cells move is a fundamental process of cancer metastasis that we still don’t understand well enough,” says Pernilla Wittung-Stafshede.

The researchers will now transfer the experiments from ​cells to small animal models and investigate whether there are other copper-binding proteins involved.​

Reference: Blockhuys, et al. (2020) Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration. PNAS DOI: https://doi.org/10.1073/pnas.1910722117 

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