New gene implicated in progression and recurrence of triple-negative breast cancer

A gene not previously associated with breast cancer appears to play a pivotal role in the growth and progression of triple-negative breast cancer (TNBC). These results suggest that targeting the gene may offer a new approach to treating the disease.

In TNBC, tumor cells do not express the genes for HER2, the estrogen receptor, or for the progesterone receptor. About 42,000 new cases of TNBC are diagnosed in the United States each year. This is about 20% of all breast cancer diagnoses.

TNBC is a very aggressive malignancy and few treatment options are available. The disease usually recurs 1 to 3 years after treatment.

Investigators studied several types of cell lines derived from breast cancers and found that the gene XBP1 was especially active in TNBC cells. The gene XBP1 played a critical role in the development of TNBC, causing cells to become malignant and enhancing disease recurrence after treatment. When XBP1 activity was suppressed in laboratory cell cultures and animal models, the size of tumors was reduced along with the likelihood of disease recurrence.

This effect was amplified when gene suppression was used in conjunction with the chemotherapy drugs doxorubicin or paclitaxel. The findings suggest that XBP1 controls the transformation of normal breast cells into malignant cells. Suppression of XBP1 expression combined with chemotherapy could be an effective treatment for triple-negative breast cancer.

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

Another regulator of transcription, HIF1-alpha, is very active in TNBC cells. The scientists found that interactions between XBP1 and HIF1-alpha might be involved in malignant transformation of normal cells.

"This shows how cancer cells co-opt the endoplasmic reticulum stress response pathway, allowing 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. "The interaction between these two critical pathways enables the cells to deal with a hostile microenvironment. This offers new strategies to target TNBC."

"We need to know whether what we observed in the laboratory models occurs 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 forward as soon as possible for the benefit of patients."

This study was published in Nature (doi:10.1038/nature13119).

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