Scientists have identified a gene that drives the development of triple negative breast cancer — an aggressive form of the disease that accounts for up to one in five breast cancer cases. The team, from Australia’s Garvan Institute of Medical Research, hopes that by finding a way to block the gene they may be able to make the cancer less aggressive.
In the study, published in Nature Communications, the researchers found that the gene known as “inhibitor of differentiation 4” (ID4) not only indicates a highly aggressive form of triple-negative breast cancer but also appears to control it.
“We found that ID4 is produced at high levels in roughly half of all triple-negative breast cancers, and that these cancers have a particularly poor prognosis,” says project leader Dr. Alex Swarbrick. “We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumor cells stop dividing.”
Triple negative breast cancers are breast cancers that lack estrogen, progesterone and HER2 receptors. Breast cancers that have these receptors can be targeted by drugs, while those without the three receptors are much more difficult to treat.
Patients that develop triple negative breast cancer typically have a higher risk of recurrence and shorter survival than patients with other forms of breast cancer. However, there appears to be a division when it comes to survival: some patients succumb to the disease within 3-5 years while others can survive disease-free for much longer than many non-triple-negative breast cancer patients.
In this new study, the researchers discovered a likely explanation for the discrepancy in survival prospects: there are actually two distinct forms of triple-negative breast cancer, appearing to originate from different cell types. While the more benign form of triple-negative breast cancer appears to originate from specialized cells, the team found that the aggressive form of the disease seems to originate from stem cells.
Could blocking ID4 make aggressive forms of breast cancer respond to tamoxifen?
Stem cells have the capacity to develop into a variety of different cell types in the body, and in many bodily tissues they divide to replenish other cells, providing the body with a form of internal repair. The manner in which stem cells are flexible and can spread into other tissues is similar to the way that many cancers operate.
Previous research has shown that breast stem cells are a vital part of breast growth and development during both puberty and pregnancy. The new study has now demonstrated that ID4 is responsible for determining whether these stem cells develop into specialist cells or not.
When ID4 is blocked in a stem cell, other genes that drive cell specialization are activated. In addition, the estrogen receptor and a number of other genes expressed by forms of breast cancer with better prognoses are also activated.
“Estrogen receptor-positive breast cancers have a relatively good prognosis because the drug tamoxifen is very effective at blocking the estrogen receptor and hence their growth,” explains Dr. Swarbrick. “We speculate, therefore, that by blocking ID4 it might be possible to turn stem-cell-like breast cancers into less aggressive breast cancers that may even respond to tamoxifen. If we are correct, that would be remarkable.”
Following their discovery, the team will now investigate ID4 in order to work out the best strategy for blocking it in humans. They are also planning a mouse study to assess whether blocking ID4 can make tumors vulnerable to tamoxifen.
“We don’t know yet whether we are seeing a real estrogen-dependent cancer after ID4 is blocked – one with an effective estrogen receptor – or just a caricature of one,” explains Dr. Swarbrick.
The team will be working in collaboration with a world expert on estrogen receptor function and studying these biochemical processes on a genome-wide scale as they attempt to fully understand the role that ID4 could play in the development and treatment of breast cancer.
In a similar study, published in Nature Communications in January, researchers from the UK identified a different gene called BCL11A that also appears to play a role in the development and progression of triple negative breast cancer. Based on their findings, the researchers proposed that BCL11A may be a “strong candidate” for development of a targeted treatment.
While further research is needed, the prospect of developing a targeted therapy for triple-negative breast cancer could be a game-changer for patients with this aggressive disease.