: Mumbai, February 12, 2025

A groundbreaking study conducted by researchers from Tata Memorial Centre (TMC), Mumbai, and the National Institute of Biomedical Genomics (NIBMG), Kalyani has uncovered key genomic factors contributing to resistance to hormone (endocrine) therapy in estrogen receptor-positive (ER+) breast cancer, the most common subtype of breast cancer in India and worldwide. The findings, recently published in Communications Biology, a prestigious Nature group journal, provide crucial insights into why some patients do not respond or stop responding to hormone therapy, paving the way for new targeted treatment strategies.

These findings offer significant clinical implications, including the potential repurposing of DNA-damaging drugs for patients who develop hormone therapy resistance. "Since resistant tumors struggle to repair their DNA, they could be vulnerable to drugs that exploit this weakness," exclaimed Dr. Sudeep Gupta, Clinician Scientist Laboratory at ACTREC and Director of Tata Memorial Centre, one of the senior investigators and co-corresponding authors of the study. "These discoveries mark an important step in personalized cancer treatment. By identifying patients at high risk of drug resistance early, we can tailor treatment strategies to improve outcomes." said Dr. Nidhan Biswas, Associate Professor and lead investigator of the study at NIBMG. "It highlights the importance of investing in fundamental cancer research to advance precision medicine for Indian patients." said Prof. Arindam Maitra, Associate Director of NIBMG who was also a principal investigator of the study.

Breast cancer remains the most frequently diagnosed cancer among women in India, accounting for 28.2% of all female cancers, with an estimated 216,108 cases in 2022. Of these, approximately 50-60% are estrogen receptor-positive, meaning the cancer cells express a protein called estrogen receptor (ER), making them susceptible to hormone therapy. While endocrine treatments, such as tamoxifen and aromatase inhibitors, have significantly improved survival rates, about 25% of patients develop resistance to these drugs, leading to disease relapse and poorer outcomes. Until now, the exact genomic mechanisms behind this resistance have remained unclear. In this study, researchers conducted whole-genome sequencing on breast tumor samples and normal tissue (buccal mucosa or blood) from 40 estrogen receptor-positive breast cancer patients treated at Tata Memorial Centre, Mumbai. Half of the patients had hormone therapy-resistant tumors, while the other half had cancers that remained controlled with hormone treatment. By applying advanced computational and bioinformatic analyses to high-throughput genomic data, the team identified two major mechanisms responsible for treatment resistance. First, the study uncovered a three-gene resistance signature—mutations in the PIK3CA, ESR1, and TP53 genes—that strongly correlated with endocrine treatment resistance. These genetic alterations enable cancer cells to survive despite anti-estrogen drugs, increasing the likelihood of recurrence and disease progression. Second, the study found that resistant tumors had defective DNA repair mechanisms, particularly in double-strand break repair. This defect leads to genomic instability and uncontrolled tumor growth, making these cancers more adaptable and resistant to treatment.

The full study has been published in Communications Biology which is accessible at: https://www.nature.com/articles/s42003-025-07606-x

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(Release ID: 2102400)