I am Auchi Inalegwu and during the past 5 years I have been working on obtaining my PhD in Biomedical Sciences. My research has focused on using different cellular and molecular techniques to study breast cancer cells, with the goal of identifying biomarkers for radiation resistance. My PhD supervisors are Prof. Winnok De Vos from the Laboratory of Cell Biology and Histology, Prof. Kris Laukens from the Adrem Data Lab, and Dr. Roel Quintens from the Radiobiology Unit at the Belgian Nuclear Research Centre.
Breast cancer is the world’s most prevalent cancer and it accounted for 2.3 million new cases and 685,000 deaths globally in 2020. Radiotherapy, which uses ionizing radiation to kill cancer cells, is especially important for the treatment of breast cancer. However, not all patients who are treated with radiotherapy will go on to live cancer-free lives. This is because cancer cells can be naturally resistant to radiotherapy or become resistant during treatment, causing treatment failure.
The cellular mechanisms underlying tumor radiation resistance are very complex and many factors are still poorly understood. Because there are still no effective biomarkers for identifying patients whose cancer is sensitive or will respond well to radiotherapy, radioresistance is only ascertained when the cancer fails to regress, spreads, or comes back (recurs) during or after treatment. This can result in new (secondary) cancers and eventual death.
Research is needed to identify biomarkers for radiation resistance (or sensitivity) that can distinguish, early-on, patients who have radioresistant cancer. This would enable these patients to receive alternative treatments that could be more effective than radiotherapy alone.
My PhD research aimed to develop and study radioresistant breast cancer cells to identify these biomarkers, with a special focus on ribonucleic acid (RNA) molecules. These RNA molecules can become dysregulated during radiotherapy and can cause cancer cells to become radioresistant.
We used human MCF7 breast cancer cells, which we treated with repeated doses of radiation (in cell culture vessels); mimicking clinical radiotherapy to develop radioresistant cells. We then identified the radiation-induced changes in the RNA levels between the radioresistant breast cancer cells and the radiosensitive breast cancer cells. We used RNA-sequencing, which is a method that helped us to identify all the messenger RNAs and circular RNAs that were dysregulated in the radioresistant cells. Messenger RNA (or mRNA) is a type of single-stranded RNA that is involved in protein synthesis. Circular RNA (or circRNA) is a type of single-stranded RNA that is circular.
Using breast cancer cell models to find biomarkers for radioresistance.
We identified 229 mRNAs and 7 circRNAs that were associated with radioresistance. Many of the mRNAs were involved in cellular mechanisms and immune response pathways that could promote cell survival and enhance radioresistance.
Patient data analysis revealed that high levels of many of these radioresistance-associated mRNAs in breast cancer patient tumors were associated with a lower probability of overall survival and relapse-free survival following radiotherapy or other therapies.
This suggests that the RNA molecules identified in our study could serve as biomarkers of therapy resistance and as target molecules for sensitizing resistant breast cancers.
Many biomarkers were also associated with tumor stage. We also identified several common and differential RNAs that are involved in the response of both radioresistant and radiosensitive breast cancer cells to single dose irradiation. These findings provide new insights into the early adaptations that are involved in the development and/or maintenance of radioresistance.
It will be necessary to further validate our biomarkers in a new patient cohort. Clinical studies should also be done to fully explore the use of these biomarkers in breast cancer treatment planning. Also, studies that characterize the specific role of these biomarkers in treatment resistance could identify new therapeutic targets for eliminating treatment resistant cancer cells.
Robust biomarkers that can predict and/or monitor the response of tumors to radiation are needed to help plan patient-specific (or ‘personalized’) cancer treatments. The results from my PhD have given us new insights that could help provide patient-specific breast cancer management.
Further reading: Fractionated irradiation of MCF7 breast cancer cells rewires a gene regulatory circuit towards a treatment-resistant stemness phenotype – PubMed (nih.gov)
Article written by Auchi Inalegwu. Edited by Dr. Bronwen Martin.