The role of extracellular vesicles in radioresistance in triple-negative breast tumors in the conventional, hypofractionated, and ultra-hypofractionated radiotherapy setting

• Grant number: 24/23183-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Wanessa Fernanda Altei
• Grantee: Mariana de Cássia Bisio
• Host Institution: Hospital do Câncer de Barretos. Barretos , SP, Brazil

Abstract

Breast cancer is a heterogeneous disease that primarily affects women. The subtype known as triple-negative breast cancer (TNBC) is recognized as the most aggressive, and the absence of ER, PR, and HER2 receptors poses a challenge for the development of new therapeutic approaches. Radiotherapy (RT) stands out as an adjuvant therapy for breast cancer, having evolved significantly in terms of technology and precision, enabling altered fractionation regimens. RT impacts the clonogenic capacity of tumor cells through the interaction of radiation with DNA, in addition to its ability to elicit an immune system response and enhance cellular communication, in which extracellular vesicles (EVs) may play a key role. EVs are anucleated particles, surrounded by a lipid bilayer, and released by tumor cells into the bloodstream, being identified as excellent protein carriers. These vesicles, particularly those originating from the endocytic pathway (exosomes), are considered potential biomarkers, as their protein profile can change after RT, with the potential to predict treatment response status. However, few studies have focused on evaluating the effect of radiation on the EV profile in the oncological context, particularly in TNBC cases and their resistance mechanisms to RT. This project aims to study the effect of different radiation doses (2 Gy, 2.67 Gy, and 5.2 Gy) on triple-negative breast cancer cells (MDA-MB-231 and MDA-MB-468), focusing on the EV profile to correlate their role as potential markers of RT resistance. The study will evaluate proliferation, cell cycle and death, DNA damage, and associate the protein profile of EVs with cellular response. It will also assess the expression of specific proteins in vesicles and investigate the effect of EVs released by irradiated cells on non-irradiated cells to contribute to a better understanding of how radiation can affect the biogenesis and functionality of EVs. The discovery of a possible molecular mechanism related to radioresistance in TNBC has significant social value, given the devastating profile of the disease and the constant need for new treatment strategies. This project will be conducted at the Barretos Cancer Hospital (Hospital de Amor - HA) in the Molecular Oncology Research Center (CPOM) and the Department of Radiotherapy, which provide the necessary team and infrastructure.