Scientists from Weill Cornell Medical College in New York, working with not-for-profit health organisation Houston Methodist, have cast new light on a deadly form of breast cancer.
The team have found that a gene not previously associated with breast cancer plays a pivotal role in the growth and progression of the triple negative form of the disease.
About 42,000 new cases of triple negative breast cancer (TNBC) are diagnosed in the United States each year, 20 per cent 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 if the gene was important to cancer’s ability to adapt and thrive in the oxygen- and nutrient-deprived environments inside tumours.
Using cells taken from patients’ tumours 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.
Dr. Glimcher, who is also a professor of medicine at Weill Cornell, said: “Patients with the triple negative form of breast cancer are those who most desperately need new approaches to treat their disease.
“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 tumours 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, the researchers were able to dramatically reduce the size of tumours and the likelihood of relapse, especially when the approach was used in conjunction with the chemotherapy drugs doxorubicin or paclitexel.
The finding suggests that XBP1 controls behaviours associated with tumour-initiating cells in a number of cancers, say the team.
They also found that interactions between XBP1 and another transcriptional regulator, HIF1-alpha, spurs cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumour cells’ growth and other behaviours typical of metastasis.
Lead author Dr. Xi Chen, a postdoctoral associate at Weill Cornell, said: “This starts to demonstrate how cancer cells co-opt the endoplasmic reticulum stress response pathway to allow tumours to grow and survive when they are deprived of nutrients and oxygen.
“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.
Co- author Dr. Jenny Chang, professor of medicine at Weill Cornell and director of the Houston Methodist Cancer Center, said: “Obviously, we need to know now whether what our group saw in models is what we’ll see in patients.
“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 and the Leukemia and Lymphoma Society.