Gene implicated in progression and relapse of deadly triple-negative breast cancer

NEW YORK—Scientists from Weill Cornell Medical College and Houston Methodist have found that a gene previously unassociated with breast cancer plays a pivotal role in the growth and progression of the triple negative form of the disease, a particularly deadly strain that often has few treatment options. Their research, published in this week's Nature, suggests that targeting the gene may be a new approach to treating the disease.

About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, about 20 percent of all breast cancer diagnoses. Patients typically relapse within one to three years of being treated.

Senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, wanted to know whether the gene—already understood from her prior work to be a critical regulator of immune and metabolic functions—was important to cancer's ability to adapt and thrive in the oxygen- and nutrient-deprived environments inside of tumors. Using cells taken from patients' tumors and transplanted into mice, Dr. Glimcher's team found that the gene, XBP1, is especially active in triple negative breast cancer, particularly in the progression of malignant cells and their resurgence after treatment.

"Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease," said Dr. Glimcher, who is also a professor of medicine at Weill Cornell. "This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better understand how this gene helps tumors proliferate and then return after a patient's initial treatment, we believe we can develop more effective therapies to shrink their growth and delay relapse."

The group, which included investigators from nine institutions, examined several types of breast cancer cell lines. They found that XBP1 was particularly active in basal-like breast cancer cells cultivated in the lab and in triple negative breast cancer cells from patients. When they suppressed the activity of the gene in laboratory cell cultures and animal models, however, the researchers were able to dramatically reduce the size of tumors and the likelihood of relapse, especially when these approaches were used in conjunction with the chemotherapy drugs doxorubicin or paclitexel. The finding suggests that XBP1 controls behaviors associated with tumor-initiating cells that have been implicated as the originators of tumors in a number of cancers, including that of the breast, supporting the hypothesis that combination therapy could be an effective treatment for triple negative breast cancer.

The scientists also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs the cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells' growth and other behaviors typical of metastasis.

"This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumors to grow and survive when they are deprived of nutrients and oxygen," said lead author Dr. Xi Chen, a postdoctoral associate at Weill Cornell, referring to the process by which healthy cells maintain their function. "It shows the interaction between two critical pathways to make the cells better able to deal with a hostile microenvironment and in that way offers new strategies to target triple negative breast cancer."

Scientists still need to study how those strategies would help women with the disease. "Obviously we need to know now whether what our group saw in models is what we'll see in patients," said coauthor Dr. Jenny Chang, professor of medicine at Weill Cornell and director of the Houston Methodist Cancer Center. "We are very excited about the prospect of moving this research forward as soon as possible for the benefit of patients."

The study was funded by the National Institutes of Health (CA112663 and AI32412) and the Leukemia and Lymphoma Society.

Also contributing to the Nature report were Junhua Mai, Haifa Shen, Melissa D. Landis, and Mauro Ferrari (Houston Methodist Hospital), Minkyung Song, Chen Tan, Stanley Adoro, and Sandra J. Shin (Weill Cornell Medical College), Dimitrios Iliopoulos and Maria Hatziapostolou (University of California, Los Angeles), Qing Zhang (University of North Carolina at Chapel Hill), Qianzi Tang (Tongji University and Sichuan Agricultural University, China), Matthew B. Greenblatt (Brigham and Women's Hospital), Elgene Lim, Min Ni, Yiwen Chen, X. Shirley Liu, and Myles Brown (Dana-Farber Cancer Institute and Harvard Medical School), Wai Leong Tam (Whitehead Institute for Biomedical Research), Dorothy Z. Hu (Massachusetts General Hospital), Bella Hu (Children's Hospital Boston).

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist.

Houston Methodist is a private non-profit health care organization comprised of a major academic medical center, six community hospitals, emergency centers, physical therapy clinics, a research institute, and a comprehensive residency program. Our flagship, Houston Methodist Hospital, was home to heart surgery pioneer Michael E. DeBakey, M.D., and has been the site of numerous medical breakthroughs, such as the world's first multiple-organ transplant in the 1960s, gene therapy for prostate cancer, and the first islet cell transplants in Texas. A legacy of medical milestones has attracted patients from around the world to Houston Methodist for more than 90 years. Houston Methodist is consistently ranked among the country's top hospitals by U.S. News and World Report. In 2013, Houston Methodist was named the top hospital in Texas and one of the country's top hospitals in 12 specialties.