Abnormalities in the genes p53 and AKT are known to promote the growth and spread of cancer, but the mechanisms behind their destructiveness are not fully understood. A research team led by Moffitt Cancer Center has made a discovery about how the activities of the two altered genes are linked—a revelation they believe could inspire new treatments for breast cancer and other tumor types.
The researchers discovered that a protein called TAp63 influences some RNA molecules, which in turn links the aberrant activities of p53 and AKT, driving tumor progression. They described the findings in the journal Nature Communications.
The Moffitt researchers previously found that TAp63 suppresses tumors and that a loss of the protein promotes cancer development. In this study, they used mouse models of breast cancer and human breast tumor samples to try to learn more about how TAp63 functions.
They focused their research on long noncoding RNA (lncRNA), a type of RNA that does not produce proteins. Previous studies had revealed a connection between TAp63 and IncRNA. To learn more, the Moffit researchers worked with scientists at MD Anderson Cancer Center, Baylor College of Medicine, the University of Houston and the University of Nottingham.
The team discovered that two lncRNAs named TROLL-2 and TROLL-3 are associated with the progression of breast cancer. Tamping them down inhibited breast cancer formation in mice.
The researchers examined 45 human samples that included normal breast tissue and various types of breast cancer. They discovered that TROLL-2 and TROLL-3 were undetectable in normal tissue. But the lncRNAs were present in the cancerous samples, with the highest levels found in the samples of invasive breast tumors.
They went on to show that when Tap63 is downregulated, there’s a complex interplay between the lncRNAs and other proteins, including one called WDR26. That stimulates AKT signaling, promoting the development of invasive breast tumors.
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Turning down the activity of TROLL-2 and TROLL-3 in mice didn’t just affect breast cancer. It also inhibited melanoma and lung cancer. They then looked for the two lncRNAs and WDR26 in human samples of several other tumor types, including ovarian and colon cancers.
“In line with our observations in breast cancer, all the malignant [tumor] types assessed had increased levels of TROLL-2, TROLL-3 and WDR26 compared to normal tissue” and benign tumors, the authors said in the study.
The researchers believe their findings could be used in several ways to diagnose and treat cancer. For example, they could help predict which patients are likely to respond to AKT inhibitors. There are several in development, including Roche’s ipatasertib, which the company is testing in breast and prostate cancers.
There could be treatment applications, as well, said Elsa Flores, Ph.D., who leads Moffit’s department of molecular oncology and cancer biology and evolution program. The findings could point to targets for “therapies against metastatic cancers with alterations in TP53 and hyperactivation of the PI3K/AKT pathway,” Flores said in a statement.
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