Dr Nakshatri on the Investigation of TONSL in Breast Cancers

Harikrishna Nakshatri, BVSc, PhD, Marian J. Morrison Professor of Breast Cancer Research, professor of surgery, Department of Surgery, professor of biochemistry and molecular biology, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, associate director of education, Indiana University Simon Comprehensive Cancer Center, full member, Tumor Microenvironment and Metastasis, discusses the investigation of TONSL (Tonsoku-like, DNA repair protein) in patients with breast cancer.

At the 2023 AACR Annual Meeting, Nakshatri highlighted research on TONSL, an upregulated immortalizing oncogene, that was found from a comparison of healthy primary breast cells and immortalized cells. Investigators questioned whether TONSL was an in vitro artifact, whether it is elevated in primary breast cancers, and whether it is related to a cancer initiation step, Nakshatri explains. They found that this gene is located on chromosome 8Q24.3, which is amplified in 20% of primary breast cancers and is duplicated in nearly 40% of breast cancers, Nakshatri emphasizes. As such, in at least 20% of breast cancers, this gene is suspected to be the cancer-initiating gene.

Investigators then introduced this gene into healthy primary breast cells and the cells became immortal, leading them to conclude that the presence of 8Q24.3 amplification may be the first sign of cancer initiation, Nakshatri says. This is one of the first genes that has been shown to have immortalization function, Nakshatri notes. Investigators also tested this suspicion in mouse models. Notably, the breast cancer field has faced challenges developing models for estrogen receptor (ER)–positive disease, Nakshatri says, adding that almost all the models that investigators created from TONSL-immortalized primary cells generated ER-positive breast cancer.