Faculty Spotlight: Xiaojing Ma, Ph.D., on Triple-Negative Breast Cancer, and the Role of UBR5 in Metastasis

What is the UBR5 protein and what’s the role it plays in tumor growth? 

UBR5 helps cells control the proteins they use to grow, respond to stress, and repair damage. UBR5 belongs to a family of enzymes called E3 ubiquitin ligases, that attach molecular tags to other proteins that change their activity or mark them for removal. 

This is part of normal cell biology, but cancer cells can really exploit it.

We want to understand how cancer cells use UBR5 to survive and how that changes their behavior. In our first study, published in Cancer Research in 2017, we identified UBR5 as a driver of triple negative breast cancer. We found extra copies of the UBR5 gene on chromosome 8 and an elevated UBR5 expression by sequencing human triple negative breast cancer patients' samples.

In that study, we found that depleting UBR5 in our very first mouse breast cancer model dramatically reduced tumor growth and metastasis. Restoring the normal UBR5 reversed these effects. This showed that UBR5 was actively supporting the tumor, providing us a foundation for developing treatment against it. 

"Our study shows that UBR5 is really important for metastatic cells to prosper at sites beyond the original tumor. If we remove UBR5, cancer cells that have reached metastatic sites will not survive."

What makes UBR5 particularly important for how we treat triple-negative breast cancer? 

UBR5 also helps cancer cells escape the immune system. Targeting it could therefore offer two complementary benefits: both weakening the cancer cell itself as well as strengthening the body's immune response against the cancer. 

Triple-negative breast cancer doesn’t respond to most immunotherapies, but we found in our 2020 study, removing UBR5 from tumor cells in a mouse model of triple negative breast cancer increased the infiltration and activity of cancer-killing cytotoxic T cells. We also found that combining UBR5 suppression with an antibody against the immune checkpoint PD-L1 protein produced much stronger anti-tumor effects. This effect is not limited to triple negative breast cancer: we also have findings in other tumor immunosuppressive cancers such as ovarian cancer and pancreatic cancer.

Many cancer patients die from cancer that has metastasized. How could targeting UBR5 help fight metastasis? 

Most cancer cells cannot successfully make the transition from the original tumor to a different environment in the body (metastasis). Our study shows that UBR5 is really important for metastatic cells to prosper at sites beyond the original tumor. If we remove UBR5, cancer cells that have reached metastatic sites will not survive.

UBR5 doesn’t have any control in whether or not a cell transitions from the primary tumor to a metastatic site, but our 2024 study demonstrated that UBR5 plays a crucial role in metastatic growth by controlling the major tumor suppressor P53 and its cell death induction function at the metastatic site. In other words, cancer cells in metastatic organs depend on UBR5 for survival against P53-induced apoptosis (cell death). 

We’re also working to better understand the relationship between P53 and UBR5. We know that when normal P53 function is lost, as happens in more than 50% of all breast cancers and many other types of cancers, many genomes start to change and become highly unstable. We want to know: “Does a cancer cell then become more reliant on UBR5?” If we can understand the connection, we can reveal something fundamental about how cancer cells adapt in metastatic sites.

"Fundamental science is so important because while you do not get instant gratification, it is important for the field, for the future of science, and for patients."

What kinds of treatments could be created because of this knowledge? 

We are developing small molecule inhibitors, specifically an E3 ligase inhibitor, to block UBR5’s typical enzymatic activity. 

Using a grant from the Department of Defense, we are also looking at ways to control and reduce UBR5 levels within a cell to target UBR5 without affecting normal cell function. We could do this because UBR5 increases in copies from 2 (which is normal) to four, or six, or eight, etc. Those high levels of protein allow cells to survive unnecessarily. Together with my medicinal chemist partner, Dr. Gan Lin, we have developed prototypes of UBR5 degraders, by using other E3 ligases that exist in the same cell to degrade UBR5. The grant will allow us to develop it further, study toxicity, improve selectivity, etc. 

Can your research be applied to other cancer types? 

Yes. UBR5 might well prove to be crucial for pancreatic cancer, ovarian cancer, and prostate cancer. Targeting UBR5 has the potential to invoke the immune system as well as target cancer cells, particularly in metastasis. 

UBR5 is a vulnerability of many types of solid tumors. We also have preliminary data in melanoma and glioblastoma. These can be particularly drug-resistant, but they are still dependent on UBR5 so that is a vulnerability we can exploit. 

Why is doing basic research like this so important for patients, even if it does not directly translate into a drug? 

Fundamental science is so important because while you do not get instant gratification, it is important for the field, for the future of science, and for patients. In our case, we started doing something very mundane – sequencing without any hypothesis – and ended up spending 10 years trying to understand how UBR5 works.

We’ve been working on UBR5 since 2015, but it had been in the database for many years before that. It wasn’t until a breast cancer surgeon came to my lab with tumor samples, and we sequenced them, that we realized how powerful a role UBR5 plays. 

We do not know how exactly, but we know that UBR5 controls P53, which is one of the most important tumor suppressors in all cancers. Before they become cancers, most cells must mutate P53 first, otherwise it would always try to induce death of these pre-malignant cells. We know that when UBR5 levels are high, P53 is very low. When UBR5 is knocked out, P53 levels go way up and tumor cells become death-prone, or senescent, or they do not proliferate. They die. 

There is tremendous potential. It will take us many years to identify the mechanisms, but once we do, the impact will be wide-ranging.