Scientists have identified a strong link between the most aggressive type of breast cancer and a gene that regulates the body’s natural cellular recycling process, called autophagy.
Based on analysis of two large breast cancer databases, reduced activity of an autophagy gene, beclin 1, was related to both a higher incidence of triple-negative breast cancer and a poorer prognosis for breast cancer patients.
The study, published in the journal EBioMedicine, is the first to document a correlation between beclin 1 and triple-negative human breast cancer and validates research in mouse models.
“We have potentially identified a new pathway to be targeted in the most aggressive, difficult-to-treat form of breast cancer,” said lead author Dr. Beth Levine, Director of the Center for Autophagy Research and a Howard Hughes Medical Institute Investigator at UT Southwestern. “These data suggest that decreased beclin 1 activity contributes to breast cancer and poor survival outcomes. As a result, therapies that increase beclin 1 activity in breast cancer may be beneficial.”
Triple-negative breast cancer – which accounts for 10 to 20 percent of breast cancer – is called such because the cancer’s cells lack estrogen and progesterone receptors and also do not have an excess of the human growth factor receptor 2 (HER2) protein on their surfaces. Chemotherapy, the standard treatment, has been limited in its effectiveness against triple-negative breast cancer.
“With low beclin 1 expression, you have up to a 35-fold higher risk of having triple-negative breast cancer. That’s really strong,” said Dr. Levine.
UT Southwestern researchers analyzed 3,057 breast cancer cases for levels of expression of beclin 1 and BRCA1, a nearby gene that is associated with inherited breast cancer. The data came from The Cancer Genome Project in the United States (1,067 cases) and the Molecular Taxonomy of Breast Cancer International Symposium in the United Kingdom and Canada (1,992 cases).
“We know that about 35 percent of all breast cancers are missing copies of both the beclin 1 and BRCA1 genes,” said Dr. Levine. “To find out which of the two genes is important, we looked at the levels of expressions of both genes and how they related to different clinical features of breast cancer. Strong associations were seen between low expression of beclin 1, but not BRCA1, and adverse clinical features.”
Along with the 35-fold higher risk of having triple-negative breast cancer, the findings showed low levels of beclin 1 activity are also linked to worse outcomes. Breast cancer patients with low beclin 1 expression levels had a 67% higher risk of dying, compared with patients with high levels.
Increasing beclin 1 activity could potentially become a new therapy for breast cancer patients, especially those with the triple-negative type, the researchers say. Several approved drugs that happen to increase beclin 1 activity are already used for other types of cancer. They include four classes of drugs: inhibitors of either beclin 1/BCL-2 binding, protein kinase B (AKT), epidermal growth factor receptor (EGFR), or HER2.
“Our study mandates the need for further research to see whether agents that upregulate beclin 1 could save more lives of breast cancer patients,” said Dr. Levine.
Funding for the research came from the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. Prof. Levine has also worked as a paid consultant to Novus Biologicals, a company that markets an antibody for beclin 1 that is used as a marker in research.