Up to 20% of hormone receptor-positive breast cancers fail to respond to standard antiestrogen therapies, a challenge that has long puzzled oncologists. A new study led by researchers at UT Southwestern suggests that an immune system protein within tumors may be fueling this resistance, opening doors to potential new treatments.
Published in The Journal of Clinical Investigation, the study identifies a protein called CXCL11, secreted by immune cells, as a key factor allowing these cancers to grow even without estrogen.
“Our findings on the role of the tumor immune microenvironment in endocrine resistance point to new therapeutic strategies to overcome resistance and improve outcomes for patients,” said Dr. Ariella Hanker, Associate Professor at the Harold C. Simmons Comprehensive Cancer Center and co-lead of the study.
Dr. Hanker co-led the research with Dr. Carlos L. Arteaga, Director of the Simmons Cancer Center, and first author Dr. Fabiana Napolitano, a former member of the Arteaga Lab.
Understanding Hormone Receptor-Positive Breast Cancer
Hormone receptor-positive breast cancers, which make up nearly 80% of all breast cancers, rely on estrogen to grow. Standard treatments block estrogen or its effects, significantly improving survival rates. However, some tumors resist therapy, often recurring after surgery, radiation, or other treatments.
To explore why, researchers analyzed 173 tumor samples from Vanderbilt University Medical Center, UT Southwestern, and Parkland Health. They compared tumors that responded to estrogen-depriving (ED) therapy with those that did not. Resistant tumors exhibited higher gene activity in immune pathways, signaling increased infiltration of immune cells like T cells and B cells.
The Role of CXCL11
Further investigation revealed that ED therapy itself can trigger tumors to release chemical signals that attract immune cells—but only in therapy-resistant tumors. The team identified CXCL11 as the key signal. Experiments showed that hormone receptor-positive cancer cells, which normally struggle to grow without estrogen, thrived in the presence of CXCL11. Similar results were observed when cancer cells were cultured with T cells.
“This study is a good bedside-to-bench example of how starting from tumors in patients treated with estrogen suppression can inform mechanistic discovery in the laboratory that, in turn, can inform new biology and treatment directions for patients with breast cancer,” said Dr. Arteaga.
A Double-Edged Sword
The findings suggest that T cells in resistant tumors act as a double-edged sword. CXCL11 promotes tumor growth, but it also recruits T cells that could potentially attack cancer cells. Traditionally, hormone receptor-positive tumors are considered “immunologically cold,” meaning immunotherapies are ineffective due to low immune activity. However, ED-resistant tumors appear to have higher T cell infiltration, suggesting they might respond better to immunotherapy—a hypothesis Dr. Hanker and her team plan to test in upcoming clinical trials.
“Eventually, doctors may use CXCL11 as a biomarker to identify which hormone receptor-positive breast cancers could benefit from immunotherapy,” Dr. Hanker said.
Funding and Acknowledgments
The study was supported by the National Cancer Institute, the Department of Defense, the Susan G. Komen Breast Cancer Foundation, the Breast Cancer Research Foundation, and other institutions. Dr. Arteaga holds the Annette Simmons Distinguished University Chair in Breast Cancer Research.
About UT Southwestern Medical Center
UT Southwestern is a leading academic medical center combining biomedical research with clinical care and education. Its faculty includes six Nobel laureates, and its physicians provide care across more than 80 specialties to millions of patients annually.
About Parkland Health
Parkland Health is one of the nation’s largest public hospital systems, offering trauma, burn, and neonatal care along with outpatient clinics and community health programs across Dallas County.
