Potential new treatment target for triple-negative breast cancer

A gene normally active only in reproductive cells may drive genetic instability in aggressive breast cancers, offering a potential new treatment target.

HORMAD1 is a gene whose expression is typically restricted to germline cells, but which is abnormally switched on in around 60 percent of triple-negative breast cancers. Researchers from the Breast Cancer Now research units at the Institute of Cancer Research, London and King's College London, have found that this incorrect activation disrupts a key safety mechanism during cell division, allowing genetic errors to be passed on.

'Although this research is still in its early stages, it offers an important step forward in understanding triple-negative breast cancer and opens the door for the development of new treatments,' said Professor Andrew Tutt, corresponding author of the study published in Nature Communications.

The team used lab-grown cancer cell lines and mouse tumour models to investigate how HORMAD1 affects mitosis, the stage of the cell cycle in which chromosomes are separated into two daughter cells. They found that, when incorrectly expressed, HORMAD1 interferes with an error correction mechanism which ensures that chromosomes are evenly divided, leading to chromosomal segregation errors and aneuploidy, where cells have an abnormal number of chromosomes.

The researchers suggest that HORMAD1-driven changes may enable cancer to grow and resist treatment. However, the study also showed that blocking the activity of certain mitotic kinases (Aurora B, MPS1 and BUB1) stopped cells with the active HORMAD1 gene from growing. In addition, tumour growth decreased in mice models of triple-negative breast cancer with the active HORMAD1 gene when the animals were treated with two Aurora B inhibitors.

Triple-negative breast cancer accounts for around 15 percent of all breast cancer cases and does not respond to hormonal or HER2-targeted therapies, limiting treatment options. Around 8000 women in the UK are diagnosed with this form of breast cancer each year.

Dr Simon Vincent, chief scientific officer at Breast Cancer Now, said: 'The findings open the door to the next crucial phase of research, where the research team can identify and test the most effective drugs or drug combinations against triple-negative breast cancer with an active HORMAD1 gene, and move the safest and most promising options towards clinical trials.'

The researchers plan to investigate whether new treatments targeting HORMAD1, as well as Aurora B, MPS1 and BUB1, could be developed and tested in more advanced models. If successful, this approach could lead to new therapies aimed at improving outcomes for patients with this aggressive form of breast cancer.