New Delhi, Aug 23: In a study that could help design better drugs for breast cancer, researchers at the Indian Institute of Science Education and Research (IISER)-Bhopal have identified the mechanism by which breast cancer cells proliferate and spread.
The team studied the regulation of a gene called ‘ESRP1’ in breast cancer. They found that there is a difference in the expression of the ESRP1 gene between normal and tumour tissues of breast cancer patients. The gene was expressed more in breast tumour tissues than normal tissues. They then explored the regulatory mechanism behind this.
The expression of a gene goes through many steps, the first of which is transcription. The ‘message’ encoded in the DNA of the gene is transcribed into RNA signals by proteins called transcription factors. The team found that in tumour tissues, a transcription factor called E2F1 that regulates transcription of ESRP1 gets up-regulated, thereby increasing its expression and eventually leading to excessive growth of breast cancer cells.
The team also found the mechanistic aspects of cancer spread to other parts of the body or what is technically called metastasis. Cancerous tumors create regions of reduced oxygen due to poor blood circulation. It has been known that such oxygen-deprived regions instigate metastasis. The IISER researchers have unraveled the mechanism behind this also. They have shown that the transcription factor E2F1 fails to bind the ESRP1 promoter in oxygen-deprived breast cancer cells, thereby downregulating the expression of ESRP1. This downregulation may cause the cancerous cells to break free from primary cancer and join the bloodstream to be carried to other parts of the body, thereby resulting in metastasis.
The study was led by Dr. Sanjeev Shukla, Associate Professor, and DBT/Wellcome Trust India Alliance Fellow in the Department of Biological Sciences at IISER-Bhopal. The work was supported by the DBT/Wellcome Trust India Alliance Fellowship Grant.
Speaking to India Science Wire, Dr. Shukla said, “Our research, for the first time, shows the reason behind an elevated expression of a key gene, ESRP1, in breast tumor tissue supporting tumor progression. Another important part of the discovery was a novel epigenetic regulatory mechanism that governs ESRP1 downregulation in hypoxic tumor tissue, which might help the cancer cells to evade the surrounding tissue and enter the bloodstream. Clearly, there is an orchestrated activation of ESRP1 in breast cancer, depending on the tumour microenvironment. Under regular oxygen conditions, cancer cells upregulate ESRP1 to help them multiply in the primary cancerous zone, but under oxygen deficiency, ESRP1 is downregulated, leading to the break-up of the cancer cells from the primary region and spread to other parts of the body. Understanding this orchestration of ESRP1 by breast cancer cells can help in devising strategic therapeutic interventions, which the IISER team continues to work towards”.
In India, breast cancer accounted for 11.1 percent of cancer deaths in 2020, necessitating the need for aggressive research into understanding and treating this malady. In cancers, it is known that some genes are activated or ‘upregulated,’ resulting in abnormal growth and proliferation of diseased cells. Cancer Epigenetics – the study of changes in gene expression that are associated with cancer – has thus assumed centre-stage in the area of cancer research in recent decades.
A report on the work has been published in the Nature group’s research journal, Oncogenesis. The paper was co-authored by Ms. Neha Ahuja, Dr. Ashok Cheemala, and Mr. SubhashisNatua, besides Dr. Shukla. (India Science Wire)