A new target for breast cancer drug development —TONSL—has been pinpointed by researchers at Indiana University Melvin and Bren Simon Comprehensive Cancer Center. The research team found the TONSL (Tonsoku-like, DNA repair protein) gene is amplified in about 20% of breast cancers, and more than 30% of metastatic cases.
Based on their research, they suggest TONSL is a regulator of epithelial cell immortalization that can play a key role in cancer initiation and is a new target for breast cancer treatment.
“TONSL has never been linked to breast cancer before. It is known that the region surrounding this gene in chromosome 8 [8q24.3] is amplified, but has never been evaluated mechanistically for cancer initiation properties,” senior author Harikrishna Nakshatri, BVSc., Ph.D., told Inside Precision Medicine.
Nakshatri is chair in Breast Cancer Research at Indiana University School of Medicine. The study was published in Cancer Research April earlier this month.
“TONSL that can make breast cells proliferate indefinitely,” he added.
He pointed out that, “Most of the cancer research to date is focused on understanding what happens when cancer progresses, but the earliest event that leads to cancer initiation has been the hardest to figure out. The very initial step in cancer is that these cells gain the ability to proliferate, and that’s the very first step that we have been able to make in models using tissue from the Komen tissue bank.”
To address this question, Nakshatri and his research team did microarray analysis of healthy breast cells from the Komen tissue bank, which is located at the IU Simon Comprehensive Cancer Center and contains about 6,000 samples, including from healthy women. Nakshatri’s lab has developed a method to grow these cells and use them as controls.
“By comparing normal cells with cells that we artificially made to grow continuously from the same donor, thus mimicking earliest event in cancer path, we have been able to identify genomic changes that happen at the earliest stage of cancer initiation,” Nakshatri said.
They found that TONSL amplification alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor–positive adenocarcinomas in mice.
Other features of TONSL amplification were: Increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB, and significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination and Fanconi anemia pathways. TONSL was also essential for growth of TONSL-amplified breast cancer cell lines in vivo.
TONSL is part of a large complex of proteins that helps to repair damaged DNA and allow cells to grow despite incomplete correction. As consequence, cells with damaged DNA continue to grow and, in the process, accumulate more mutations and become cancerous.
The researchers found that the TONSL protein works with a protein called FACT. In the breast cancer models the team created with the TONSL amplification, breast cancer cells were highly susceptible to an existing drug (CBL0137) that targets the FACT complex.
“Breast cancer is a diverse disease with different subtypes, and some patients respond to the different treatments, and others do not. With 20 percent of breast cancer patients having amplification of this gene, more research is very important to target TONSL,” said Aditi Khatpe, first author of the paper and an IU School of Medicine doctorate student.
