Oncogenes and tumor suppressor genes have long been implicated in tumor development. Oncogenes drive cells to grow faster and survive longer, while tumor suppressor genes put the brakes on cells to stop their growth and prevent cancer from forming.
“Traditionally, much attention has been focused on studying mutations in these genes that can lead to cancer development, but this approach has not been sufficient to explain all cancers,” said Dr. Wei Li, professor at Baylor College of Medicine and member of the Dan L Duncan Comprehensive Cancer Center. “We took a different approach.”
Li and his colleagues did not look to identify alterations or mutations that change the oncogenes or tumor suppressor genes themselves, but mechanisms that could disrupt the normal regulation of the expression of these genes and the proteins that carry out the genes’ functions. They focused on a phenomenon widely active in cancer cells called mRNA 3ʹUTR shortening, or shortening of the long strand of mRNA.
“The prevailing hypothesis, which is based solely on studies of cancer cell lines grown in the laboratory, but not on tumors directly from patients, is that mRNA 3ʹUTR shortening induces oncogene activation. Recent data has challenged that view,” said first author Dr. Ping Ji, assistant professor of biochemistry and molecular biology at the University of Texas Medical Branch (UTMB) in Galveston. “Here, we studied samples directly from breast cancer patients and found evidence suggesting that the major role of mRNA 3ʹUTR shortening is in mediating repression of tumor suppressor genes, rather than inducing oncogene activation.”
The researchers studied this mechanism by combining two independent approaches.
“We used both a computational biology approach to analyze large amounts of genetic data along with classical molecular experiments in the laboratory,” said first author Dr. Hyun Jung Park, who was a postdoctoral associate in the Li lab during the development of this project and currently is an assistant professor of human genetics at the University of Pittsburgh. “Our statistical model accurately predicted gene expression changes mediated by mRNA 3ʹUTR shortening in human breast cancer.”
The laboratory studies provided a functional validation of these predictions confirming the major role of 3’UTR shortening plays in leading to the repression of tumor suppressor genes, including PTEN a gene well-known in breast and other cancers.
“This study is highly significant because it sheds light on new ways that tumors disrupt gene expression networks. It was shocking to me to see the lengths that cancers such as breast tumors will go in order to reduce the expression of tumor suppressor genes,” said senior author Dr. Eric Wagner, associate professor of biochemistry and molecular biology at UTMB. “My lab and the Li lab have collaborated for many years, and I hope that we will continue to drill down on the mechanisms underlying cancer gene expression regulation.”
We think that our findings can lead to new treatment or prevention strategies to overcome the effects of the 3’UTR shortening mechanism and thus restore the expression of PTEN and other tumor suppressor genes involved in breast cancer,” Li said.
Find all the details of this study in the journal Nature Genetics.
Other contributors to this work include Soyeon Kim, Zheng Xia, Benjamin Rodríguez, Lei Li, Jianzhong Su, Kaifu Chen, Chioniso P. Masamha, David Baillat, Camilla R. Fontes, Ann-Bin Shyu and Joel R. Neilson.
This work was supported by the US National Institutes of Health grants R01HG007538, R01CA193466, RO1GM046454 and U54CA217297, the Cancer Prevention Research Institute of Texas (CPRIT) grant RP150292, CPRIT RP100107, CPRIT RP140800 and the Welch Foundation grant AU-1889.