Tailoring treatment for triple-negative breast cancer

April 13, 2020

Immunotherapies have revolutionized treatment for people with a variety of cancers. But when given to those with triple-negative breast cancer (TNBC), a particularly aggressive form of the disease, less than 20% respond.

"A big question in the field has been, Why are the rest not responding?" says Rumela Chakrabarti, an assistant professor at Penn's School of Veterinary Medicine.

In a new paper in Nature Cell Biology, Chakrabarti and colleagues illuminate the molecular details at play. They found a signaling pathway which could be exploited in TNBC patients to better target therapies in the future. Using a mouse model of the disease that mimics key characteristics of human disease, they showed that losing the activity of the protein ELF5 promotes the activity of another protein, interferon-gamma receptor 1. Stabilized Interferon-gamma receptor 1 leads to activated interferon gamma signaling, which in turn leads to increases in tumor aggression and spread, which could be mitigated with therapeutics that block interferon gamma signaling.

"This was an eye-opener," says Chakrabarti, "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."

Chakrabarti had a deep familiarity with the biology of the ELF5 protein. She began studying it more than a decade ago as a postdoctoral researcher at the State University of New York at Buffalo, finding that its normal function supported pregnancy and lactation. More recently, in 2012 she and colleagues published a previous report in Nature Cell Biology showing that ELF5 could suppress a key transition that occurs to enable breast cancers to spread.

That earlier work, however, did not focus on TNBC specifically, in part because scientists had lacked an effective mouse model. Over the course of three years, Chakrabarti's team developed a preclinical TNBC model that recapitulated two hallmarks of the disease: its propensity to spread and the influx of immune cells that accompanies tumor growth.

In the current study, the researchers found that, when these TNBC mice's tumors also lost the function of the ELF5 protein, their disease course resembled that of human patient's even more closely. "Losing ELF5 made the disease very metastatic and very aggressive," says Chakrabarti.

To elucidate the molecular happenings that resulted in a more dangerous form of TNBC, Chakrabarti and colleagues examined the RNA that was being expressed in tumor cells of the TNBC mice whose tumors lost ELF5 expression. They found increased activity of the interferon-gamma pathway, caused, they believe, by an increase in expression of that protein's receptor. This loss also led to an accumulation of neutrophils, a type of immune cell, which has immune suppressive function. In contrast, normal mammary cells that retained ELF5 had low levels of interferon gamma signaling.

Blocking this signaling using an antibody against the interferon gamma receptor 1, or by genetically manipulating tumor cells to express lower levels of the receptor caused tumors to grow and spread more slowly.

Finally, to determine whether these findings in a mouse model may be relevant to humans, the research team looked at genetic and protein data from patients to determine their level of ELF5 and interferon gamma receptor expression. Patients with lower ELF5 and higher receptor levels, they observed, fared poorer; their cancers tended to spread sooner around their bodies.

The findings, Chakrabarti says, should be considered carefully by clinicians who are using interferon gamma and immunotherapies to treat cancer patients.

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

In future work, Chakrabarti's group will be diving in deeper into the immunology of TNBC, examining the role that different immune cells are playing in driving cancer metastasis and aggression. They also hope to see whether what they found regarding interferon gamma signaling in TNBC holds true in other tumor types, such as kidney and ovarian cancers.
Rumela Chakrabarti is an assistant professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine.

Chakrabarti's coauthors on the paper were first author Snahlata Singh, Sushil Kumar, Ratnesh Kumar Srivastava, Ajeya Nandi, Gatha Thacker, Hemma Murali, Sabrina Kim, Mary Baldeon, Mario Andres Blanco, and Serge Fuchs of Penn Vet; John Tobias, Rizwan Saffie, and Luca Busino of Penn 's Perelman School of Medicine; Temple University's M. Raza Zaidi; and Satrajit Sinha of the State University of New York at Buffalo.

The work was supported by the National Cancer Institute (grants CA193661 and CA237243).

University of Pennsylvania

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.