Dr. Sarat Chandarlapaty and team showed that a known family of enzymes that play an important role in how our bodies respond to an infection are also linked to breast cancer drug resistance
Breast cancer is often treated with hormone therapy (also known as endocrine therapy) and other targeted drugs like CDK4/6 or HER2 inhibitors. Many cancers respond well to these treatments, but for reasons we don’t fully understand yet, they can adapt and stop responding—a process known as drug resistsance. Researchers are investigating the underlying processes behind drug resistance, since understanding these molecular mechanisms will improve long-term outcomes for patients.
A new study from BCRF investigator and Scientific Advisory Board Chair Dr. Sarat Chandarlapaty published in Nature Genetics offers some clues as to why this happens.
Dr. Chandarlapaty and his team observed a specific pattern of DNA mutations in many breast tumors that became significantly more common after tumors are exposed to therapy. Intriguingly, these mutational patterns mirrored those created by a known family of naturally occurring proteins called APOBEC3 enzymes. Dr. Chandarlapaty and his colleagues were interested in learning how these enzymes are involved in drug resistance.
What are APOBEC3 enzymes?
APOBEC3 enzymes are a family of proteins that play a role in the immune system’s arsenal against viruses. They respond to an infection by mutating viral DNA, which disables the virus’ ability to replicate or grow. But they can also unintentionally mutate human DNA by mistaking it for viral DNA in rapidly dividing cells. These mutations lead to a distinct mutational pattern—called a mutational signature—after cells copy the altered DNA. That can then drive cancer progression or drug resistance.
Abnormal elevation of APOBEC3 activity has been observed in bladder, head and neck, and breast cancers. Prior studies have associated higher expression levels of APOBEC3 enzymes with poorer outcomes and hormone therapy resistance in estrogen receptor–positive breast cancer.
What did the study find?
The team analyzed DNA from 3,880 tumor samples from people with breast cancer. Across all tumor samples studied, the most dominant mutational signature observed was attributed to APOBEC3 activity. APOBEC3 activity was more prevalent in metastatic tumors compared to primary tumors in hormone receptor (HR)–positive and triple-negative disease. Because metastatic breast cancer has typically progressed despite earlier treatment, it is more likely to have become resistant to therapy.
Further, in HR-positive metastatic breast tumors that exhibited APOBEC3 mutational signatures, progression-free survival—the time during and after treatment where breast cancer does not get worse—was found to be shorter. This means their cancer progressed more quickly than in patients whose tumors lacked the APOBEC3 signature.
Laboratory experiments showed that APOBEC3 activity accelerated tumor cells’ capacity to develop drug resistance. In some models, APOBEC3 activity led to mutations in DNA that disabled key cancer-control genes, like the retinoblastoma protein 1 (RB1) gene, which acts as a tumor suppressor. These results align with prior studies that demonstrated that tumors with mutations in RB1 correlated with the individual developing drug resistance.
Dr. Chandarlapaty and team also showed that, in the majority of samples, the APOBEC3 mutational signature was detectable before treatment began, indicating enzyme activity occurs early on, before a tumor has been exposed to therapy. This is consistent with the team’s prior findings, which showed APOBEC3 signatures in pre-invasive breast lesions. It was also different from other cancer types where APOBEC3 enzymes are activated by the targeted therapy.
Why is this discovery important?
Activation of APOBEC3 enzymes can generate many mutations over time, creating genetic diversity in cancer cells and giving tumors more chances to evolve and survive treatment. While many studies focus on individual genes causing drug resistance, this research shows a systematic cause—a mutational process driven by APOBEC3 enzymes—may initiate many resistance-causing mutations across the genome.
Unlike many resistance mechanisms that emerge in response to therapy, APOBEC3 activity appears to be present in breast tumors before treatment begins. This early presence is significant—it means we may be able to predict which tumors are prone to developing resistance and intervene earlier to prevent it.
“BCRF funding was critical to enabling our group to spend the years needed to generate models that faithfully resemble the way breast cancers function,” Dr. Chandarlapaty said. “This not only allowed us to prove the role of APOBEC3 enzymes but is now also facilitating our efforts to target breast cancers manifesting APOBEC mutagenesis.”
What does this mean for patients?
The findings reported here could influence strategies that assess a person’s risk of aggressive cancer. For example, patients may be screened for APOBEC3 mutational signatures at diagnosis, and those with high levels may receive more aggressive or tailored treatment to preempt resistance.
Results reported in this study may eventually lead to new clinical trials to test therapies that target APOBEC3 directly or reduce its mutagenic impact. And oncologists could provide more treatment options if APOBEC3 can be used as a biomarker to decide whether to switch or add treatments early, before tumors evolve overt resistance.
Drug resistance remains a pervasive problem in treating breast cancer. Studies like this one are essential to unraveling the biology of drug resistance to ultimately prevent it. Identifying patients who are likely to develop resistance will help guide treatment decisions early and more precisely. In this way, the results have the potential to not only improve responses to therapy but also reduce the chances of recurrence for people with breast cancer.
