There are three major subtypes of breast cancer: hormone receptor-positive, HER2-positive, and triple-negative. Although there are focused therapy approaches for the first two, triple-negative breast cancer patients have limited options. In a recent study, scientists discovered that the nuclear receptor TLX may be utilized for medicinal purposes.
Researchers have been able to find effective treatments for both hormone receptor-positive and HER2-positive breast cancer, and the prognosis for patients with these forms of the disease is favorable. Triple-negative breast cancer, on the other hand, lacked a clear drug development target. We are searching for novel targets because the five-year survival rate is lower than that of other breast cancer subtypes.”
The Nelson laboratory focuses in the research of nuclear receptors, which are a class of proteins that govern a variety of biological processes. They chose to go through many nuclear receptors in order to locate one that could be utilized to target triple-negative breast cancer.
“TLX has previously been identified as a contributor to brain and prostate cancer. “However, when we examined clinical data, we discovered that triple-negative breast cancer patients with higher expression of TLX have superior survival rates,” said Adam Nelczyk, the study’s lead author and a doctoral student in the Nelson lab.
The researchers next conducted experiments on triple-negative breast cancer cell lines to investigate if increasing TLX expression may reduce the defining characteristics of cancer, including tumor development, migration, invasion, and metastasis.
The researchers stacked the cells on plates, allowed them to develop, and then assessed the DNA content to determine cell growth. Using a similar setup, they monitored migration, but added a scratch between the cells and recorded time-lapse photographs to determine how rapidly the cells were able to close the distance. In both of these studies, cells expressing TLX demonstrated decreased proliferation and migration.
Cancer cells are also notable for their ability to break the borders between tissues, a process known as invasion, which results in the formation of tumors in both neighboring and distant tissues, a phenomenon known as metastasis. To study this phenomena in cell lines, researchers utilized special gel-coated chambers that simulate the tissue barrier; cancer cells produce substances that aid them in breaking past the barrier. They discovered that TLX+ cells were less invasive.
“The decrease in metastasis is especially significant because metastatic disease progression is the leading cause of death,” Nelson added.
The same hallmarks were also evaluated in mouse models, along with RNA sequencing and histology tests to measure alterations in TLX expression. Mammary gland tumors were transplanted into the mice. “The observations validated our initial findings that mice with elevated TLX expression had less proliferative activity,” Nelczyk explained.
Although the results are encouraging, the mouse models do not fully replicate human behavior. “The mice we use lack a complete immune system because they must be able to produce human cells, therefore they may not fully replicate sickness,” Nelson explained. “However, in conjunction with the patient data, they suggest that TLX is an excellent therapeutic target. Next, we must corroborate our findings in human subjects.”
Unfortunately, triple-negative breast cancer is a disease with multiple subtypes. Therefore, the models utilized by the researchers may not be applicable to other triple-negative cancer types. They intend to focus their future study on the other subcategories.
Nelczyk, A.T., et al. (2022) The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple- negative breast cancer. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease. doi.org/10.1016/j.bbadis.2022.166515.