A gene known to regulate the immune system and the cellular stress response has been implicated in the growth and progression of triple-negative breast cancer (TNBC), a highly aggressive malignancy with limited treatment options. The gene, called XBP1, helps TNBC tumors activate a crucial metabolic pathway. This pathway is called HIF1α, after the hypoxia-inducing factor. By accessing the HIF1α pathway, cells can better tolerate adverse conditions such as oxygen and nutrient deprivation.
TNBC tumors risk being starved of oxygen and nutrients because they are poorly vascularized. However, by co-opting the HIF1α pathway, TNBC tumors may improve their odds of survival. They may even acquire the ability to outlast adverse conditions and resurge. That is, they may account for the ability of TNBC return after the end of treatment.
If TNBC tumors could be prevented from accessing the HIF1α pathway, they might more easily succumb to treatment.
This finding was presented March 23 in Nature, in an article entitled “XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.” This article, the work of researchers from Weill Cornell Medical College and Houston Methodist Cancer Center, described how the researchers 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 TNBC cells from patients.
When the researchers suppressed the activity of the gene in laboratory cell cultures and animal models, they 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 scientists also found that interactions between XBP1 and HIF1α spurs cancer-driving proteins. Silencing XBP1 in the TNBC cell lines reduced the tumor cells’ growth and other behaviors typical of metastasis.
In their article, the authors wrote: “We have uncovered a key function of XBP1 in the tumorigenicity, progression and recurrence of TNBC, and have identified XBP1’s control of the HIF1α transcriptional program as the major mechanism. XBP1 pathway activation correlates with poor patient survival in TNBC patients, indicating that [unfolded protein] inhibitors in combination with standard chemotherapy may improve the effectiveness of antitumor therapies.”
“Patients with the triple-negative form of breast cancer are those who most desperately need new approaches to treat their disease,” said senior author Laurie H. Glimcher, M.D., who is 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.”
“Obviously we need to know now whether what our group saw in models is what we'll see in patients,” said coauthor Jenny Chang, Ph.D., 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.”