A large multidisciplinary team led by researchers at the Garvan Institute of Medical Research and the University of New South Wales in Australia recently published in the journal Nature Communications that the so-called “triple-negative breast cancers” are in fact two distinct disorders that probably originate from different cell types. The study is entitled “ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype.”
Around 15% of all diagnosed breast cancers are considered triple-negative breast cancers, characterized by the lack of the receptors commonly targeted in chemotherapy — estrogen, progesterone or human epidermal growth factor receptor 2 (HER2). These cancers are frequently non-responsive to targeted therapeutic drugs and patients usually have a higher risk of disease recurrence and a shorter survival rate than patients with other types of breast cancer.
Curiously, patients with triple-negative breast cancer can be classified into two categories: those that succumb to the disease within 3 to 5 years despite treatment, and those that remain disease-free for a longer period in comparison to the average non-triple-negative breast cancer patient (at least 8 years after the diagnosis). The recent finding that in fact triple-negative breast cancers represent two distinct diseases may explain these two different categories.
Researchers found that the aggressive form of triple-negative breast cancer seems to originate from stem cells, whereas the more benign form seems to arise from specialized cells. Stem cells are plastic and flexible cells that can differentiate into several types of specialized cells, and are capable of proliferating and spreading into other tissues, features also commonly observed in cancer cells.
In the study, researchers report that a gene called inhibitor of differentiation 4 (ID4) is responsible for determining whether a stem cell remains a stem cell, or whether it differentiates into a specialized cell. In addition, researchers found that this gene is associated to the highly aggressive form of triple-negative breast cancer.
“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,” said the study’s senior author Dr. Alexander Swarbrick in a news release. “We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumor cells stop dividing.”
Researchers found that when ID4 in a stem cell is “switched off,” cancer growth is halted and other genes are “switched on,” namely genes that lead to cell specialization. Blocking ID4 also leads to the expression of the estrogen receptor 3 and other genes linked to the best-prognosis breast cancer.
“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” explained 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.”
The team’s next goal is to determine the best therapeutic strategy to block ID4 in humans and to conduct therapeutic experiments in rodent animal models to test the hypothesis that switching off ID4 sensitizes the tumor to Tamoxifen treatment.