UTSW study links deficiency of cellular housekeeping gene with aggressive forms of breast cancer

January 30, 2015

DALLAS - Jan. 30, 2015 - UT Southwestern Medical Center 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 online 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 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, who holds the Charles Cameron Sprague Distinguished Chair in Biomedical Science and is co-senior author of the study with Dr. Yang Xie, Associate Professor of Clinical Science.

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 also correlated with worse outcomes.

"Patients with breast cancer and low beclin 1 expression had a 67 percent increase in the risk of dying from breast cancer compared with patients who had higher levels of beclin 1 expression," Dr. Xie said.

Increasing beclin 1 activity could, therefore, become a new therapy for breast cancer patients, especially those with the triple-negative type. Several approved drugs that happen to increase beclin 1 activity are already used for other types of cancer. They included 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," Dr. Levine said.

Dr. Levine's research team studies genes involved in the autophagy process and their roles in cancer, aging, infections, and neurodegenerative diseases, while Dr. Xie's UT Southwestern lab focuses on improving cancer treatments through statistical and computational analysis of biological and clinical data.
-end-
Co-lead authors from UT Southwestern were Dr. Hao Tang, Assistant Professor of Clinical Science, and Dr. Salwa Sebti, a postdoctoral researcher in Internal Medicine. Other UT Southwestern researchers included graduate student and visiting junior researcher Rossella Titone; Dr. Yunyun Zhou, a computational biologist in Clinical Science; Dr. Theodora Ross, Professor of Internal Medicine and Director of UT Southwestern's Cancer Genetics Program; Dr. Guanghua Xiao, Associate Professor of Clinical Science; and Dr. Milton Packer, Professor and Chair of Clinical Sciences and holder of the Gayle and Paul Stoffel Distinguished Chair in Cardiology.

The work was supported by grants from the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. Dr. Levine has received consulting fees from Novus Biologicals.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering approximately 2,800, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.

This news release is available on our home page at http://www.utsouthwestern.edu/home/news/index.html

To automatically receive news releases from UT Southwestern via email, subscribe at http://www.utsouthwestern.edu/receivenews

UT Southwestern Medical Center

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.

Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.

More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.

Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.