Research Projects

Breast cancer remains a major cause of cancer-related mortality among women worldwide, with particularly high death rates in low- and middle-income countries (LMICs). In India, the burden is disproportionately high in underserved regions such as Central India, where access to early diagnosis, molecular testing, and targeted treatment is limited. Despite advances in diagnostics and therapy, many patients, especially those with triple-negative breast cancer (TNBC) or homologous recombination (HR) deficiencies, experience poor outcomes. While PARP inhibitors have shown benefits in BRCA-mutated cancers, issues such as resistance and high cost limit their broader impact. A key therapeutic gap lies in targeting cancers that rely on alternative DNA repair pathways. One such mechanism is theta-mediated end joining (TMEJ), an error-prone process activated in HR-deficient tumors. DNA polymerase theta (Polθ), encoded by POLQ, is a core TMEJ component and is frequently overexpressed in aggressive breast tumors. High POLQ expression correlates with genomic instability, poor prognosis, and resistance to therapies causing DNA-damaging. Recently developed Polθ inhibitors offer promise in preclinical models, inducing synthetic lethality in BRCA-deficient cancers and overcoming PARP inhibitor resistance. This project will evaluate the expression and functional role of POLQ, its repair partner LIG3, and regulatory non-coding RNA miR-210 in breast cancer. Public datasets will be analyzed to correlate gene expression with clinical features and outcomes. Stratification based on POLQ and HR gene expression will help identify TMEJ-high, therapy-resistant subgroups. Functional assays including gene knockdown, MTT, clonogenic survival, γ-H2AX foci, comet assay, and nano luciferase-based MMEJ reporters will assess the impact on DNA repair and therapy response. miR-210 targeting of POLQ will be tested using luciferase assays. These findings aim to uncover new biomarkers—including potentially indigenous markers relevant to the Central Indian population—for identifying patients who may benefit from Polθ-targeted therapies, especially those unresponsive to current DNA repair inhibitors. This approach could reduce overtreatment, lower toxicity, and offer more personalized, effective care. Importantly, by enabling low-cost gene expression-based stratification, such strategies would be particularly valuable in LMICs where access to high-cost therapies is limited. If successful, this research will advance the understanding of DNA repair dependencies in breast cancer, support the development of novel targeted therapies, and promote precision oncology approaches that are accessible and cost-effective. Ultimately, it may contribute to reducing breast cancer mortality by guiding treatment selection through practical and affordable molecular diagnostics, especially in resource-constrained regions like Central India.