Breast cancer has been a predominant topic among the research community, and over the years newer, more effective treatments have evolved. Yet, there are many risk factors associated with developing breast cancer, including age, genetics, diet, and if you are a smoker. It is believed that prevention may be the best approach to fighting this disease.
Today, the field of epigenetics has matured enough to deserve attention for preventing cancers, particularly breast cancer. Previous studies have shown that epigenetic marks found in a simple blood test may determine a woman’s predisposition to breast cancer. In addition, women with mutations to their BRCA1 gene who breastfeed their children for at least one year might epigenetically lower the child’s risk for developing breast cancer down the line.
In a recent study published in Nature Medicine, scientists from the Imperial College London set out to further determine why some tumors become impervious to chemotherapy treatment, and found that tumor cells use epigenetics to hide from the drugs that seek to destroy them.
In this study, Dr. Luca Magnani and his team examined the role of a transcription factor called Yin Yang1, which stimulates gene activation and is found universally in each cell of the body. Initially, the researchers were unsure if Yin Yang1 was a tumor suppressor or promoter, as it has been linked to different patient outcomes. So, they supplemented the use of the gene editing tool CRISPR, along with other techniques to profile breast cancer tumors from 37 treated and untreated patients. Some of the treated patients experienced drug resistant metastasis.
The researchers concentrated on the genes that were being switched on and off in estrogen-receptor positive breast cancer, the most common form of breast cancer in which the estrogen hormone stimulates the growth and metastasis of tumors. They examined 13 tumors from patients whose cancer had metastasized, and 34 tumors from patients whose tumors remained stagnant.
The team discovered that cancer cells depend on Yin Yang1 far more than regular cells do, perhaps due to the high rate of cellular division. Interestingly, they also found that tumors switch on different genes as they progress and become more aggressive.
Yin Yang1 switches on a gene called SLC9A3R1, and together these genes can actively promote tumor growth and allow them to hide from drugs.
The team attributes the gene switch to increased levels of the histone mark H3K27ac found at the enhancer region of Yin Yang1. Histone acetylation is a mechanism that adds acetyl groups to lysine residues found on the DNA, which loosens the chromatin, leaving it accessible for transcription to turn the gene on.
This discovery is significant for diagnosis and treatment development because it emphasizes the importance for a patient to have a second biopsy if the cancer has spread. Tumor cells evolve their gene expression as they progress, which allows them to successfully hide from treatment. “Our results suggest tumours switch different genes on and off as they progress, and can fundamentally change their ‘appearance’” Dr. Magnani said. “Therefore if a tumour becomes more aggressive, and spreads around the body, we would advise always taking a second biopsy. The cancer might have changed significantly in this time, and would respond to different treatments. Although taking a second biopsy when a patient’s cancer relapses is becoming much more common, it’s still not happening all the time.”
The outlook on the fight against breast cancer is a relatively positive one. The number of breast cancer related deaths has been in a steady decline since the early ‘90s due to the improvements made in research, early detection, and treatments. Dr. Magnani expects to apply the methods and information gained from this study to track the epigenetic modifications that occur at the enhancer regions in breast cancer cells, with the hopes of improving diagnoses, and developing more effective treatments.
If you would like to donate to breast cancer research, please visit the National Breast Cancer Foundation.
Source: Luca Magnani (2018) Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer. Nature Medicine 24, 1469–1480
Reference: Kate Wighton “Breast cancer fuelled by mysterious Yin Yang protein” Imperial College London. 23 July 2018 Web.