Study: Tailoring Treatment for Triple-negative Breast Cancer is Necessary

Triple-negative breast cancer (TNBC) is an aggressive form of the disease with no known treatment. Although immunotherapies have been effective when treating a variety of other cancers, less than 20% of those with TNBC respond to such treatments.¹

In a new study published on April 13 in Nature Cell Biology, researchers found a signaling pathway that could be used in patients with TNBC to enhance therapies in the future.¹

On a mouse model of the disease, researchers showed that losing the activity of the protein ELF5 promoted the activity of another protein, interferon-gamma receptor 1. The stabilized interferon-gamma receptor 1 then led to activated interferon gamma signaling, which can also lead to an increase in the spread and intensity of the tumor. The results showed that this increase could be mitigated with therapeutics that effectively block interferon gamma signaling.¹

“This was an eye-opener because often interferon gamma has a protective effect in cancer and is commonly given as a cancer therapy to some patients. It works well in certain cancer types, but for particular subtypes of triple-negative breast cancer, we see that blocking interferon gamma may be the best strategy for patients,” said Rumela Chakrabarti, MS, PhD, an assistant professor at Penn's School of Veterinary Medicine, in a press release.²

While studying at the State University of New York at Buffalo, Chakrabarti developed a familiarity with the biology of the ELF5 protein. Early on in her research, she found that the normal function of the ELF5 protein supported pregnancy and lactation, according to the press release. More recently, she worked on a team that published a study in Nature Cell Biology that showed how ELF5 could suppress the occurrence of a key transition that allows breast cancers to spread.²

In Chakrabarti’s earlier work, she was not able to focus on TNBC due to the lack of a mouse model of the disease. Over a period of 3 years, her team was able to develop an effective TNBC mouse model, which allowed them to focus their research. In the new study, the researchers were able to demonstrate the efficacy of this mouse model, as the TNBC mice’s tumors lost the function of the ELF5 protein, which demonstrated that their disease course closely resembled a human patient's.¹

“Losing ELF5 made the disease very metastatic and very aggressive,” Chakrabarti said in a press release.²

In order to understand what occurred to cause this more dangerous form of TNBC, Chakrabarti’s team analyzed the RNA in the tumor cells of the TNBC mice who lost ELF5 expression in their tumors. Upon their analysis, the researchers found a level of increase in activity of the interferon-gamma pathway. They explained that this may cause an increase in the expression of the protein's receptor.¹

The study authors found the loss of ELF5 expression also led to an accumulation of neutrophils, which is a type of immune cell that has an immune suppressive function. Normally, mammary cells that retain ELF5 have low levels of interferon gamma signaling. The researchers discovered that by blocking this signaling, either by using an antibody against the interferon gamma receptor 1 or by genetically manipulating tumor cells to express lower levels of the receptor, they caused tumors to slow their growth.¹

Chakrabarti’s team went on to assess the relevance of applying this new information to humans by looking at genetic and protein data from patients and determining their level of ELF5 and interferon gamma receptor expression. The researchers found that patients with lower ELF5 and higher receptor levels had cancer cells that tended to spread sooner.¹

These results demonstrated the need to tread with caution when using interferon gamma and immunotherapies as a treatment for patients with cancer, Chakrabarti explained in a press release.²

“This is telling us that we need to target patients more selectively when we treat them. It could be that if someone has low ELF5, they should be given an interferon-gamma signaling blocking therapy in addition to their immunotherapy,” Chakrabarti said.²

In the future, Chakrabarti’s team plans to study the immunology of TNBC further, specifically in regard to the role different immune cells play in developing cancer metastasis and aggression. They also hope to research whether what they learned regarding interferon gamma signaling in TNBC applies to other tumor types, such as kidney and ovarian cancers.²

REFERENCES

• Singh S, Kumar S, Srivastava RK, et al. Loss of ELF5—FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signaling. Nature Cell Biology. 2020. doi: 10.1038/s41556-020-0495-y.
• Tailoring treatment for triple-negative breast cancer [news release]. ScienceDaily; April 13, 2020. sciencedaily.com/releases/2020/04/200413144051.htm. Accessed April 14, 2020.