‘Junk DNA’ offers a new therapy target for aggressive breast cancer

Pseudogenes are segments of DNA that have high similarity to known functional genes but do not produce functional proteins. For decades, these large portions of DNA were dismissed as “junk DNA” with little or no functional significance. 

In a new study published in the Proceedings of the National Academy of Sciences, researchers at the University of Chicago have identified BRCA1P1, one such pseudogene, as an important regulator of immune response. It helps cancer cells avoid detection by the immune system by dampening antiviral immune pathways. The discovery of BRCA1P1’s involvement in immune regulation opens the door to developing new approaches to treat cancer.

Breast cancer gene 1 (BRCA1) is a well-known tumor suppressor gene, involved in the repair of DNA damage and maintaining genomic stability. Mutations in the BRCA1 gene have been reported to increase the risk for breast cancer. BRCA1P1, a fusion pseudogene derived from the BRCA1 and RPLP1 (ribosomal protein) genes, is widely expressed in various cancer cells. 

“We found that BRCA1P1 is right in the BRCA1 genomic region, but it’s not functioning like BRCA1, it’s doing something completely different,” said Olufunmilayo Olopade, MD, Walter L. Palmer Distinguished Service Professor of Medicine and Human Genetics. 

A hidden regulator of cancer immunity

Olopade’s lab has previously reported higher levels of BRCA1P1 gene expression in human breast cancer cells compared to normal tissue. In the current study, they found that it is also expressed across a wide range of cancers, including brain, colon, endometrial, head and neck, kidney, lung, prostate, ovarian, and blood cancers such as B-cell lymphoma, diffuse large B-cell lymphoma, acute myeloid leukemia, and chronic myeloid leukemia.

Instead of producing proteins, BRCA1P1 generates RNA molecules, many of which form stable circular structures that interact with key immune signaling pathways. These RNA molecules suppress antiviral defense mechanisms, which are normally responsible for detecting and eliminating abnormal cells. 

“We initially thought BRCA1P1 would have similar biological functions as BRCA1, but as we spent more time, we found immune regulatory function,” said Yoo Jane Han, PhD, staff scientist in Olopade’s lab and first author of the study. “Antiviral immunity doesn’t just fight viruses. It also helps trigger the immune system to attack cancer cells.”

To understand how BRCA1P1 regulates immune responses, the team collaborated with a virus specialist to conduct experiments with antiviral pathways, helping establish the link between this pseudogene and the body’s innate immune response. At the same time, they collaborated with chemists to design specialized RNA-targeting molecules, such as antisense oligonucleotides, to selectively inhibit BRCA1P1 without affecting the parent BRCA1 gene.

When BRCA1P1 was blocked with inhibitors, researchers found activation of antiviral signaling pathways, leading to the production of immune-stimulating molecules like interferons and cytokines. This, in turn, led to increased cancer cell death and enhanced sensitivity to chemotherapy. At the same time, tumors became more visible to the immune system. The team observed increased infiltration of immune cells, including T cells and macrophages into tumors—key players in inducing an effective antitumor response.

From “junk” to therapy

There are about 15,000 to 20,000 pseudogenes in the human genome, a number comparable to protein-encoding genes. For years, these genes have been ignored because of their unknown function, but with growing evidence of their functional roles, they are now recognized as important as protein-coding genes, providing a major shift in understanding pseudogenes and their role in disease.

“This study was a groundbreaking discovery for our lab because we have been working on the BRCA1 region for a long time, and now we have a new way to look at that region to see how BRCA1P1 might be functioning to regulate our own immune system,” Olopade said.

The study showed that targeting BRCA1P1 did not harm normal cells. Instead, cancer cells responded strongly to chemotherapy, suggesting a potential therapeutic target for breast cancer. The research also demonstrated the effectiveness of BRCA1P1 inhibitors in more accurate research models, including patient-derived tumor organoids and humanized mouse models, which closely mimic human disease. 

A decade in the making

The discovery builds on years of work studying the BRCA1 region of chromosome 17, a hotspot for genetic alterations in breast cancer. Although BRCA1 itself is well known for its role in DNA repair, the surrounding genomic landscape has not been well understood. 

“We have been trying to figure out how all the genes like BRCA1, ERBB2 (HER2), and TP53 (p53) that are so critical to breast cancer could all just be on the same part of chromosome 17,” Olopade said. “With advances in genome sequencing and computational biology, we were able to see a bigger picture, which led us to this unexpected finding.”

A key strength of this study was the use of patient-derived tumor organoids—miniature, three-dimensional models grown from patients’ cancer cells that allowed researchers to test findings in models that closely reflect human disease. These organoids were made possible through the generosity of patients, including individuals who, chose to donate tissue samples to support research aimed at accelerating new treatments, even while facing advanced breast cancer. 

“Our patients are true partners in this work—their willingness to contribute, even in the most difficult circumstances, allows us to move discoveries closer to real-world impact,” Olopade said. “This patient-centered approach is further supported by funding from the National Institutes of Health and advocacy organizations, whose investments have been critical in advancing innovative, patient-focused cancer research.”

The team is now working to refine strategies to target BRCA1P1 and explore how they can be combined with existing treatments, including immunotherapy and chemotherapy.

The study, "Regulation of Antiviral and Antitumor Immunity by the BRCA1 Pseudogene in Human Cancers," was supported by the National Institutes of Health, Susan G. Komen Foundation, and Breast Cancer Research Foundation.

Additional authors from the University of Chicago include Jing Zhang, Maryam Shariff, Sulin Wu, Galina Khramtsova, Long Chi Nguyen, Daniel Peiffer, Nansheng Li, Anna Lewicka, Matthew Moore, and Joseph Piccirilli.