Scientists have identified an overactive protein that may provide a target to treat basal-like breast cancer, a deadly carcinoma that is resistant to many types of chemotherapy.
Basal-like cancer is a category that includes a number of different breast cancers, including the highly aggressive form called triple negative cancer.
However, when they looked at patterns of gene expression in basal-like cancer and another cancer subtype, they found that a small number of genes are activated by STAT3 protein signaling in basal-like breast cancers but not in luminal breast cancers.
“You can’t treat breast cancer as one disease,” says Curt M. Horvath, professor of molecular biosciences and of microbiology-immunology and medicine at Northwestern University.
“Cancer describes many molecular processes that have gone wrong. We have teased out from large amounts of data that STAT3 activity correlates with distinct patterns of gene expression in one type of breast cancer but not in another.”
The findings published in the online early edition of the Proceedings of the National Academy of Sciences, suggest a clinical study should be conducted of a STAT3-inhibiting drug in patients with basal-like and luminal cancers, Horvath says. Currently there are no pills or injections targeting STAT3 for breast cancer patients.
Previous research has found the STAT3 protein to be overactive in many breast cancers, but its role has not been well understood. The new research is the first reported study to compare breast cancer subtypes and gene expression patterns associated with STAT3 in the tumors of human patients.
The analysis is based on breast cancer patient data taken from the Cancer Genome Atlas. Researchers emphasize that this is a statistical analysis and that the findings need to be verified with careful laboratory and clinical experiments.
“The Cancer Genome Atlas is a really rich and growing database of publicly available data created to help us understand cancer,” Horvath says. “It allows basic scientists to ask interesting questions about cancer and contribute to clinical care.”
Horvath and Robert W. Tell, a postdoctoral fellow in Horvath’s lab, observed that there are many clearly visible patterns of common gene expression—where certain genes are turned on and certain genes are turned off—in the basal-like cancers. Those clear patterns were not seen in the luminal cancers.
“This opens up the possibility that cancer subtype-specific signaling is driven by STAT3, and that STAT3 inhibitors may be more effective in patients diagnosed with basal-like cancers than in those with luminal cancers,” Horvath says.
STAT3 stands for “signal transducer and activator of transcription 3,” a transcription factor (a protein) encoded by the STAT3 gene in humans. In addition to its known roles in cancerous cells, STAT3 also is an essential mediator of cytokine and growth factor signals in normal cells that are important for diverse processes including immunity and inflammation.
The researchers identified 84 genes that are expressed differently in basal-like cancer tumors as compared to luminal cancer tumors. These genes are highly representative of the immune response and inflammation processes, Horvath says, and are consistent with the role of STAT3.
The intensive analysis used data from 825 breast cancer patients from across the country, each with hundreds of data points. The data included protein expression, protein phosphorylation, which indicates which signaling pathways are activated, and messenger RNA and microRNA expression.
To sort through the vast amounts of data, the researchers used Quest, a high-performance computing system at Northwestern. The computer cluster they used offered the equivalent of the processors and random-access memory (RAM) of eight powerful desktop computers linked together.
The H Foundation and a Signal Transduction in Cancer Training Program of the National Cancer Institute supported the research.
Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors, Published on Journal 《PNAS》in Jul 28, 2014.