Researchers Find Clues to How Breast Cancer Can Infiltrate the Brain

Pictured: Johanna Joyce

Johanna Joyce, who heads a laboratory in the Sloan Kettering Institute’s Cancer Biology and Genetics Program

Most cancer deaths occur when the disease spreads, or metastasizes, from the original tumor site to a distant location. In breast cancer patients, metastasis to the brain can occur months or years after seemingly successful treatment of the primary tumor.

Now Memorial Sloan Kettering researchers have found that a protein called cathepsin S may play a key role in the spread of breast cancer to the brain. A complex interplay between breast cancer cells and certain surrounding cells called macrophages induces both cell types to secrete increased levels of cathepsin S, an enzyme that promotes the cancer cells’ ability to metastasize.

In addition to potentially helping doctors predict which breast cancer patients are at increased risk for brain metastasis, the discovery, published recently in Nature Cell Biology, suggests that cathepsin S could be an important target for new drugs.

“Brain metastasis is a devastating development of breast cancer, and the current therapeutic options are limited,” says cancer biologist Johanna Joyce, who heads a laboratory in the Sloan Kettering Institute’s Cancer Biology and Genetics Program and led the study. “To have an increased understanding of the process but also a target that we can think about going after is exciting.”

Interplay Both Home and Away

In order to take root and grow, metastatic cancer cells must find ways to exist in a potentially less nurturing, even hostile, setting. Researchers have known that cancer cells rely partly on their microenvironment — the noncancerous cells, molecules, and blood vessels that surround a tumor — in order to survive and grow. But much less has been known about how the microenvironment may confer upon cancer cells the capacity to metastasize. Dr. Joyce and first author Lisa Sevenich, a member of Dr. Joyce’s laboratory, were also interested in how these noncancerous cells at metastatic sites react when they encounter the tumor cells. To investigate these questions, the research team studied mice implanted with human breast cancer cell lines that are known to spread to the brain, bone, and lung. They looked at how both the tumor and its surrounding microenvironment change during metastatic progression.

Pictured: Robert Bowman and Lisa Sevenich

Robert Bowman and Lisa Sevenich, coauthors of the study and members of Dr. Joyce’s laboratory

The cancer cells and surrounding cells were subjected to genetic analysis to see which genes were more active than normal. In mice with brain metastases, the cathepsin S gene was significantly overexpressed. Interestingly, the tumor cells produced more cathepsin S at the beginning of metastasis and then tapered production, in parallel with a progressive increase in macrophage cathepsin S levels within the brain.

The reciprocal relationship suggests that breast cancer cells become equipped for metastasis through the two-way signaling between tumor cells and macrophages in the microenvironment. The interplay between the two cell types takes place both at the primary tumor location and at the metastatic site in the brain.

“The increase in cathepsin S expression occurs in a subset of cells in the primary tumor, and we infer that those are tumor cells that go on to seed brain metastases,” Dr. Joyce says. “But the increase is really most pronounced at the metastatic site in the brain. We view it as bidirectional education over the course of metastasis between both components of the tumor — the cancer cells and the cells in the microenvironment are each changing in response to signals from the other.”

The researchers showed that cathepsin S enables the cancer cells to penetrate through the blood-brain barrier, a densely packed vascular structure that protects the brain from most large molecules in the blood. Cathepsin S is a protease, a type of enzyme that degrades proteins. The researchers found that cathepsin S cleaves a protein called (JAM)-B, which normally helps hold cells in the blood-brain barrier together. The higher levels of cathepsin S presumably negate (JAM)-B’s effect and allow the cancer cells to penetrate the barrier.

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Blocking Cathepsin S to Stop Metastasis

To validate the role of cathepsin S in promoting brain metastases, the researchers inhibited it with experimental drugs. This significantly reduced the development of brain metastasis in the animals. To be effective, the drugs needed to block cathepsin S in both the cancer cells and the macrophages. Dr. Joyce says that although related cathepsin S inhibitors are already in clinical trials for autoimmune diseases such as rheumatoid arthritis, “they are not currently being tested in cancers. We hope that may change soon.”

In addition, she says she is intrigued that genes for proteases besides cathepsin S are expressed at higher-than-normal levels in the tumor and microenvironment cells they analyzed. “I’m really interested in whether these other proteases might play complementary roles in helping brain metastases grow after cathepsin S has allowed them to take the critical step of entering the brain,” she says.

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This research was funded by the Center for Metastasis Research at Memorial Sloan Kettering, the National Institutes of Health under grants CA126518 and CA148967, and other sources.


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Hi, I'm currently in treatment for triple negative breast cancer metastatic to bones. Would there be a way that someone like me can be tested to see if I have catispin protein? Blood test? Scan? I'm currently under the care of Dr Gluck at the University of Miami.

Cori, thank you for your comment. The research described in this story is still in an early stage and there is currently no clinical test for cathepsin S in breast cancer patients.

Is there anything, we, the breast cancer community, can do to assist in getting these clinical trials expanded into breast cancer research more quickly?
Thank you for the information.

Debbie, the keys to moving cancer research into clinical trials more quickly are increased awareness and increased funding. If you are interested, we encourage you to get involved in these areas.

You may also be interested in learning about our efforts to extend our clinical trials to more people more quickly by reading the following blog posts:

MSK Transforms Cancer Research and Care Delivery

MSK Announces Unprecedented Alliance

Making Clinical Trials More Efficient, Informative, and Effective…

Thank you for your comment.

Do you know what the purpose of the cathepsin S is in the body in the first place? Only for enabling communication between macrophages and cancer cells for purposes of metastasis or could there be a more benign purpose which could be affected if it is inhibited?

Will my oncologist and/or surgeon check brain and bones to see if cancer has spread from the original breast tumor?

I have a friend how had triple negative breast cancer that has now metastasized to the brain. She is in treatment in Fort Collins. Are there any clinical trials of cathepsin S blockers that she could enroll in, or other types of relevant clinical trials?

Rose, we’re sorry to hear about your friend. We recommend that she go to to find any trials that she may be able to enroll in and that are also somewhere she is able to go geographically. Thank you for your comment.

My wife Sally has stage 4 breast cancer that has metastasized to her ribs and brain. She recently had targeted radiation on the brain legions that resulted in a reduction in size. She has now been accepted for a clinical trial using Keytruda. Do you know any success rates for patients using this drug to combat breast cancer ?
Thank you

Hi David, the trials using Keytruda as a treatment for breast cancer are still very early and it’s too soon to tell how effective the drug will be in this setting. Thank you for your comment, and best wishes to you and your wife.

On paxataxol weekly for metasatic breast cancer to the bones so if there is a clinical trial to help me in any way please contact me


What is the current status after 4 years on Blocking Cathepsin S to Stop Brain Metastasis.
Has there been any progress?

Dear Nili, this research is still in early stages. Thank you for your comment.