Researchers of the University of Illinois (United States) have discovered that the nuclear receptor TLX can potentially be used for therapeutic intervention against triple negative breast cancer.
Breast cancer is classified into three main subtypes: hormone receptor positive, HER2 positive and triple negative. Although there are therapeutic approaches aimed at the first two, options for triple-negative breast cancer patients are limited.
“Researchers have been able to develop good therapies for hormone receptor-positive and HER2-positive breast cancer, and the long-term survival of patients diagnosed with these cancers is quite good. On the other hand, breast cancer triple negative has lacked an obvious target to develop drugs against. We are trying to find new targets because the five-year survival rate is worse than that of other types of breast cancer, “explained Erik Nelson, one of the leaders of the study, which has been published in the scientific journal ‘Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease’.
Nelson’s lab specializes in the study of nuclear receptors, a class of proteins that regulate a number of biological processes. They decided to search through different nuclear receptors to identify one that could be used to attack triple-negative breast cancer.
“TLX has been previously characterized in brain and prostate cancer as being a driver of these. However, when we looked at the clinical data, we saw that triple-negative breast cancer patients who have a higher expression of TLX have better survival rates“, details Adam Nelczyk, lead author of the study.
The researchers then carried out experiments in triple-negative breast cancer cell lines to determine whether increasing TLX expression could reduce the classic hallmarks of cancer: tumor growth, migration, invasion, and metastasis.
To measure growth, the researchers plated the cells, allowed them to grow, and then measured the DNA content. They also measured migration using a similar setup, but introduced a scratch between the cells and took time-lapse images to see how quickly the cells were able to close the gap. In both tests, cells expressing TLX showed reduced growth and migration.
Cancer cells are also famous for their ability to break down barriers between tissues, known as invasion, leading to the formation of tumors in adjacent tissues, as well as tissues that reside far away, a process called metastasis.
To measure this phenomenon in cell lines, the researchers used special gel-coated chambers that mimic the tissue barrier; cancer cells secrete factors that help them break through. They found that TLX+ cells invaded to a lesser extent.
“Reducing metastasis is especially important because most mortality is due to metastatic progression of the disease,” says Nelson.
The same characteristics were also measured in mouse models, along with the RNA sequencing, to measure changes in TLX expression, and histological studies. The mice were grafted with tumors in the mammary glands. “The data corroborated our initial findings, showing that mice with higher expression of TLX had reduced proliferation,” notes Nelczyk.
Although the results are promising, the mouse models do not fully reflect what occurs in humans. “The mice we used don’t have a complete immune system because they have to be able to grow human cells, so they may not recapitulate the disease perfectly. However, together with the patient data, they indicate that TLX is a good drug target. Next, we will need to confirm our findings in humans,” says Nelson.
Unfortunately, triple negative breast cancer is a heterogeneous disease, and there are several subcategories. Therefore, the models the researchers used may not be applicable to other triple-negative cancers. They hope to focus on the other subcategories in their future studies.
“We want to better understand what TLX does, not only in cancer cells. We have some indication that TLX may also modulate the activity of certain types of immune cells. Since we couldn’t get a full picture on our models, that’s the main goal of our next series of studies,” Nelczyk concludes.