Thymidine kinase 1 (TK1) as a biomarker for breast cancer prognosis

Breast cancer is one of the most diagnosed cancers in the European Union, with an estimated 374,800 women and 4,400 men diagnosed in 2022 (data from the European Commission EU Breast Cancer Report, October 2022). It is a complex disease with various subtypes and clinical outcomes, and accurate prognostic markers are crucial for tailoring treatment strategies and predicting patient outcomes such as survivorship and chances of recurrence.

Thymidine kinase 1 (TK1) is an enzyme involved in cell proliferation, and it plays an active role in the development and progression of breast cancer. In recent years, TK1 has been used extensively in clinical trials as a potential biomarker to monitor disease progression and patient responses to treatment, to a good degree of success.

In this article, we will review what TK1 is, its role in cellular proliferation in the context of breast cancer, and how measuring thymidine kinase activity can aid in breast cancer prognosis.

Diagnosis refers to the identification and classification of a disease or condition, while prognosis refers to the likely course and outcome of a disease.

In the context of breast cancer, patients receive a diagnosis when a healthcare professional confirms the presence of cancerous cells or tumours in their breast tissue. This may involve several steps, such as medical imaging, a physical examination, and a tissue biopsy. Once breast cancer has been diagnosed, the patient will receive a prognosis, which involves the predicted behaviour of the cancer cells such as its development rate and chances of survival.

The thymidine kinase enzyme found in human cells have two isoforms – thymidine kinase 1 (TK1) and thymidine kinase 2 (TK2). They have different cellular locations and functions, and TK1 is used as a potential biomarker for assessing cell proliferation, while TK2 is not as extensively studied in association with cancer prognosis.

TK1 is an enzyme that is expressed during the S-phase of the cell cycle, when DNA replication occurs. Its activity is closely associated with cell proliferation and division. In cancer cells, TK1 activity is thus upregulated to support rapid cancer cell growth and proliferation as the disease develops.

TK1 has been studied extensively by medical researchers in relation to breast cancer prognosis. In its role as a biomarker, TK1 levels can be measured to support in the identification of tumour characteristics, disease stage and progression, and patient responses to different treatments.

In breast cancer patients, elevated TK1 levels have been correlated with larger tumour sizes, which in turn indicates a more advanced disease progression and poorer prognosis. Higher TK1 levels have also been associated with more aggressive cancer cells that are likely to spread more quickly, leading to a worse prognosis.

Advanced breast cancer stage is associated with a worse prognosis, and elevated TK1 levels are observed in late-stage breast cancer patients. Many medical studies have also shown that breast cancer patients with higher TK1 levels tend to have overall lower rates of survivorship and shorter disease-free survival.

Breast cancer is more likely to recur as well, in patients with elevated TK1 levels, and this is particularly true for the hormone receptor-positive and triple-negative subtypes of breast cancer.

Finally, elevated TK1 levels have been associated with poor response to treatment. Typically, medical professionals measure TK1 levels at regular intervals during the course of treatment to understand the impact and effectiveness of therapies.

Breast cancer patients with higher TK1 levels post-treatment indicate they are responding poorly to chemotherapy, endocrine therapy, and targeted therapies. This can lead to disease progression and poorer outcomes if the poor response is not followed up and changes in treatment are not made.

Measuring TK1 levels can provide great insight into disease progression and treatment effectiveness for breast cancer patients. Knowing this, we explore a few measurement techniques used by medical professionals to aid prognosis.

TK1 activity and levels can first be measured using serums and plasma samples.

A widely used technique is the Enzyme-Linked Immunosorbent Assay (ELISA), which involves using specific antibodies that recognise TK1. These antibodies capture and detect the enzyme, so that medical researchers can quantify the level of TK1 and use colorimetric or fluorescent detection to measure the intensity of the signal produced. ELISA-based TK1 assays have been validated for clinical use, and there have become commercially available for a while.

Another widely used technique is Radioimmunoassay (RIA), which is used to measure TK1 levels in biological samples. In RIA, a radiolabelled TK1-specific antibody is used to measure the level of TK1 in the sample. The radiolabelled antibody binds to TK1, and the level of radioactivity is proportional to the amount of TK1 present in the sample.

Finally, Polymerase Chain Reaction (PCR)-based techniques are also widely employed. This technique involves reverse transcription of RNA into complementary DNA (cDNA). Following this, TK1 cDNA is amplified using specific primers so that they can be quantified. Medical researchers then use fluorescent signals to identify the initial level of TK1 mRNA in the sample.

There is a consistent association between TK1 levels and breast cancer prognosis, and there is available evidence that suggests higher TK1 levels are associated with poor prognosis. Nevertheless, while there is plenty of recognised research material on TK1 as a potential prognostic biomarker in treating breast cancer, it is crucial to understand that it is most effective when used in combination with other tools, such as various imaging and screening methods, regular monitoring of symptoms, and treatment such as therapies and surgeries.