DDNews Cancer Research Exclusive: A trio of culprits for triple negative breast cancer

HOUSTON—Triple negative breast cancer is a subtype of breast cancer that tests negative for estrogen receptors, progesterone receptors and HER2. Given this characteristic, the cancer does not respond to hormonal therapy or HER2-targeted therapies, which severely limits the options available for patients with this disease. Added to that is the issue that triple negative breast cancer tends to be more aggressive than other types of breast cancer, with a higher tendency toward metastasis and recurrence; triple negative breast cancer is also usually 'basal-like,' and such cancers tend to be higher grade and more aggressive. According to Breastcancer.org, approximately “10 to 20 percent of breast cancers, more than one out of every 10, are found to be triple negative.”

Survival outcomes for this type of cancer are low, as well; Breastcancer.org notes that “A 2007 study of more than 50,000 women with all stages of breast cancer found that 77 percent of women with triple negative breast cancer survived at least five years, versus 93 percent of women with other types of breast cancer. Another study of more than 1,600 women published in 2007 found that women with triple negative breast cancer had a higher risk of death within five years of diagnosis, but not after that time period.”

Given the obvious need for new therapies for this cancer, a recent discovery by researchers at Baylor College of Medicine of a network of proteins that triggers triple negative breast cancer, proteins that could provide new therapeutic targets, is welcome news. The study's results appeared in Cell Reports, in a paper titled “The Oncogenic STP Axis Promotes Triple-Negative Breast Cancer via Degradation of the REST Tumor Suppressor.”

Thanks to genetic screening, the researchers identified three proteins that collectively trigger the degradation and malfunction of the tumor suppressor protein RE-1 Silencing Transcription factor, or REST. The trio of proteins consists of SCYL1, TEX14 and PLK1, which are also known as the STP axis. Dr. Thomas “Trey” Westbrook, an associate professor of biochemistry and molecular biology at Baylor and the corresponding author of the study, and his colleagues discovered the first link between REST and human cancer in 2005.

“There are currently no targeted therapies for triple negative breast cancer. Chemotherapy is the standard of care and, while it works for some people, most patients suffer adverse side effects and relapse of the cancer,” said Dr. Kristen Karlin, a post-doctoral associate in Westbrook’s lab and the study’s lead author. “In Dr. Westbrook’s lab, one of our major goals is to identify the molecular drivers of triple negative breast cancer that represent therapeutic entry points for patients with the disease. These therapeutic entry points represent targets for the development of new medicines.”

“We found that while REST protein is lost (in triple negative breast cancer), there are no changes to the DNA or RNA that one often sees in tumor suppressors. This suggests something happens at the protein level,” Karlin added.

“During the course of normal development, the transcription factor REST is responsible for restraining neuronal identity (inhibiting the expression of neuronal genes) in cells that are not destined to be neuronal cells,” Westbrook explains. “In the nervous system, there is a very specific mechanism by which REST protein is lost so that the neural features required for proper development can be switched on and neurons can behave like neurons. In the remainder of the body, REST acts as a safeguard preventing other cell types from acquiring neural characteristics.”

However, outside of the nervous system, Westbrook explains, “REST is a tumor suppressor in many cancers,” including breast cancer.

“We discovered that REST plays a prominent role in colon cancer and loss of REST function can facilitate cancer progression. One of the key discoveries we made in this story is that REST protein is lost in a large fraction of breast cancers, particularly in the aggressive triple negative breast cancer subtype,” Westbrook notes. “Unlike other cancers in which REST is inactivated, we found that REST protein is lost in breast cancer via a less-common mechanism. In breast cancer, REST protein becomes very unstable. Once we uncovered the mechanism by which REST is inactivated in breast cancer, we focused our efforts on identifying the upstream signaling axis, the STP axis, which causes the REST protein to become unstable. The STP axis, which is comprised of SCYL1, TEX14 and PLK1, cooperates to inactivate the REST tumor suppressor.”

“PLK1 directly modifies REST and marks this protein for degradation,” said Karlin. “Interestingly, SCYL1 and TEX14 are necessary for this process as well. They act as scaffolds for PLK1 to complete the process.”

While PLK1 has been previously linked to cancer, Westbrook says neither SCYL1 nor TEX14 have been implicated in cancer before and calls their findings “truly novel discoveries as it was not expected for SCYL1 or TEX14 to have a role in human disease.”

When the team inhibited the STP axis in the lab, it resulted in increased REST protein levels, which in turn impaired triple negative breast cancer formation, tumor progression and metastasis. In the reverse, expression of the axis resulted in low REST protein levels and poor clinical outcomes in human tumor samples.

“Inactivation of REST leads to cancer progression; however, the mechanisms by which this occurs is still largely unknown. REST is best known for its role in inhibiting neuronal gene expression. Interestingly, there are certain neuronal genes and functions that are aberrantly turned on in triple negative breast cancers. Some of these REST-regulated gene products are very important in neural development and in the survival of neurons. Our work describing the frequent loss of REST protein in breast cancer leads to the hypothesis that there might be certain neuronal genes that are being aberrantly turned on, and the breast cancers are using those gene products as their own sort of survival network,” says Westbrook.

The team's discovery offers a potential target for this cancer type in PLK1, for which drugs are already being developed; PLK1 is typically associated with mitosis or cell division, and has been widely studied. According to Westbrook, “several PLK1 inhibitors have been developed and are currently being tested in the clinic.”

“While these inhibitors have shown promise in preclinical animal models of cancer, they often have dose-limiting toxicities in patients,” he explains. “We believe many of the toxicities associated with PLK1 inhibitors occur because PLK1 has a wide range of cell-essential functions. Our work implies that there is one specific function of PLK1, causing inactivation of the tumor suppressor REST, that seems to be selectively important in cancer. If there are individual, cancer-specific functions of PLK1, then there is potential to develop PLK1-targeted therapies that are effective but with fewer toxicities.”