Abnormalities in New Molecular Pathway May Increase Breast Cancer Risk
A new molecular pathway involving the gene ZNF365 has been identified, and abnormalities in that pathway may predict worse outcomes for patients with breast cancer, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.
“Genomic instability is an increased tendency for abnormal changes in DNA, like the addition of extra copies of chromosomes, DNA breaks, and mutations,” said Ji-Hye Paik, PhD, Assistant Professor in the Department of Pathology and Laboratory Medicine at Weill Cornell Medical College in New York. “Because these genetic abnormalities increase the chances for developing a tumor, it is fundamentally important to understand the molecular basis of genomic instability in cancer for prognosis and therapy.”
p53–ZNF365–telomere Pathway
Critically short telomeres activate cell death, or apoptosis, mediated by the tumor-suppressor gene p53. This process is critical in the suppression of cancer, and dysfunctional telomeres can cause chromosomal abnormalities and cancer.
Using cells designed to be cancer-prone because of defective telomeres, Dr. Paik and colleagues demonstrated that p53 activates ZNF365 to maintain genomic stability. The researchers found that cells deficient in ZNF365 showed signs of incomplete doubling of DNA, causing abnormal cell division and unequally divided chromosomes. They concluded that because ZNF365 promotes the timely resolution of cell division, its loss led to an abnormal number of chromosomes called aneuploidy, which is implicated in many diseases including cancer.
“Our study is the first to demonstrate molecular mechanisms underlying the p53–ZNF365–telomere pathway and to show how alterations in this pathway may lead to increased cancer risk,” said Dr. Paik. “Understanding this pathway provides novel therapeutic opportunities for cancers.”
ZNF365 Expression Lowest in Triple-negative Breast Cancer
To understand the role of ZNF365 in cancer, Dr. Paik and colleagues used data available from The Cancer Genome Atlas and analyzed the expression of ZNF365 in 49 triple-negative breast cancers, the most aggressive form of breast cancer, and 300 non–triple-negative breast cancers. They found that expression of ZNF365 was lowest in triple-negative breast cancer, and it remained high in non–triple-negative breast cancer.
Using data from a larger cohort of 2,978 women from The Cancer Genome Atlas, the researchers also found that among women who had a 10-year, relapse-free survival, those with a high expression of ZNF365 had a 26% higher survival advantage. Further, when the researchers analyzed for the presence of ZNF365 in a tissue microarray containing 18 normal breast tissues, 141 triple-negative breast cancers and 145 non–triple-negative breast cancers, ZNF365 was present in normal breast tissues and non–triple negative breast cancers, but its expression declined in triple-negative breast cancers.
According to Dr. Paik, this study is the first to determine the expression of ZNF365 in different types of breast cancers, and because it predicts disease prognosis, ZNF365 may be a potential biomarker for patient stratification.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
