Gene Implicated in Progression and Relapse of Triple-Negative Breast Cancer
Scientists from Weill Cornell Medical College, New York, and Houston Methodist, Houston, 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. The research by Chen et al, published in Nature, suggests that targeting the XBP1 gene may be a new approach to treating the disease.
About 42,000 new cases of triple-negative breast cancer are diagnosed in the United States each year, about 20% of all breast cancer diagnoses. Patients typically relapse within 1 to 3 years of being treated.
XBP1
Senior author Laurie H. Glimcher, MD, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, wanted to know whether XBP1—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 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. “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.”
Study Details
The investigators 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 doxorubicin or paclitaxel.
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. This supports 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 triple-negative breast cancer 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 Xi Chen, PhD, a postdoctoral associate at Weill Cornell. “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.”
Clinical Implications Unknown
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 Jenny Chang, MD, 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."
Dr. Glimcher is the corresponding author of the Nature article.
The study was funded by the National Institutes of Health and the Leukemia and Lymphoma Society.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
